Pharmacokinetics of clodronate in renal failure.

The pharmacokinetic parameters describing the fate of one intravenous clodronate (disodium dichloromethane diphosphonate) dose was studied in 24 normal subjects and in 24 patients with different degrees of renal insufficiency. The aim of the study was to derive data for adjustment of dosage in relation to renal function. Disodium clodronate in serum and urine samples was analyzed by capillary gas chromatography with mass-selective detection. The renal clearance (CLR) of clodronate was highly dependent on renal function and declined successively with declining glomerular filtration rate (GFR). Plasma clearance (CLP) declined, too, but to a lesser degree than CLR. The impairment of renal function resulted in decreased cumulative urinary elimination of clodronate and increased total areas under the serum concentration-time curve (AUC0-infinity). Hence, as the renal elimination of clodronate diminishes with decreasing GFR, there is a related retention of the substance. As a result of the present study, the following dosages are recommended: creatinine clearance (CLCr) from 50 to 80 ml/minute, 75-100% of normal dose; CLCr 12-50 ml/minute, 50-75% of normal dose; and ClCr < 12 ml/minute, 50% of normal dose. The results must be interpreted with caution in patients with malignancy and severe skeletal disease, in whom the nonrenal clearance may vary markedly.

Rapid normalization of antipyrine oxidation by heme in variegate porphyria.

Effects of heme on hepatic xenobiotic drug metabolism were investigated in eight subjects with variegate porphyria. A single infusion of heme arginate (3 mg/kg heme) reversed rapidly the prolonged mean elimination half-life of antipyrine from 27.2 to 12.7 hours (p less than 0.001) and increased total clearance from 0.23 to 0.44 ml/min/kg (p less than 0.001). Excretion of 6 beta-hydroxycortisol and D-glucaric acid increased significantly during heme infusion. Excretion of urinary porphyrin precursors increased during the antipyrine test but was normalized by heme. It is concluded that in variegate porphyria a partial block in heme biosynthesis results in subnormal capacity of P450-associated monooxygenases, but this is easily normalized by exogenous heme.

A controlled study with taltrimide and sodium valproate: valproate effective in partial epilepsy.

Taltrimide was compared with valproate and placebo in 17 patients with intractable epilepsy being on carbamazepine monotherapy. Taltrimide (400 mg/day), valproate (1000 mg/day) or placebo were added to the treatment for periods of 3 months using a randomized cross-over design. Serum carbamazepine concentrations remained within the therapeutic range throughout the trial. Thirteen patients completed the study. In partial epilepsy of 7 the seizure frequency was reduced by 27% during valproate (p less than 0.05), compared with placebo, while no improvement was found during taltrimide. In 6 with primary generalized epilepsy, the number of seizures was reduced by 49% during taltrimide and by 38% during valproate, but neither effect was significant, compared with placebo. Headache was reported by 3 patients while on taltrimide. One with hypersensitivity history developed petecchiae and nasal bleeding during taltrimide and, therefore, the treatment was stopped. The three other interruptions were independent of taltrimide. Thus, the only statistically significant effect in this study was that of valproate in partial epilepsy.

Haem arginate improves hepatic oxidative metabolism in variegate porphyria.

1. The elimination of antipyrine was investigated before and after intravenous administration of haem arginate (3 mg haem kg-1 day-1 on three or four successive days) to six patients with variegate porphyria in remission. 2. Haem arginate decreased the faecal content of protoporphyrin from 557 +/- 91 to 118 +/- 32 (mean +/- s.e. mean) and of coproporphyrin from 144 +/- 19 to 19 +/- 3 nmol g-1 dry weight. 3. Before haem treatment antipyrine elimination half-life was long (30.5 +/- 5.6 h), but the treatment decreased it to 6.3 +/- 0.8 h. Antipyrine clearance increased from 0.25 +/- 0.05 to 1.03 +/- 0.11 ml min-1 kg-1 (P less than 0.001), being 4.6 times higher after haem arginate infusions. 4. The volume of distribution of antipyrine did not change. 5. The severe impairment of hepatic mixed function oxidase activity even in the symptomless stage of porphyria indicates cautious dosage of drugs primarily eliminated by hepatic oxidative reactions.

Bioavailability of rectally administered carbamazepine mixture.

The relative bioavailability of carbamazepine mixture was studied after oral and rectal administration to healthy subjects. The absorption was significantly slower after the rectal than after the oral route but the total bioavailability was similar provided the mixture was not defaecated within 2 h of administration. We conclude that carbamazepine can be administered rectally, e.g. to postoperative patients in doses corresponding with oral doses.

Haem arginate: a new stable haem compound.

Intravenous administration of haem in acute hepatic porphyrias inhibits the induction of delta-aminolaevulinic acid synthase, reduces the formation of potentially harmful metabolites of porphyrin synthesis and corrects the haem deficiency. Typically, haem therapy has been given in the form of haematin--haem dissolved in alkali. Such haematin solutions are, however, extremely unstable. Thus, the rapid decomposition of this therapeutic agent may have been responsible for the ineffectiveness of treatment in some clinical states and adverse reactions may have been caused by haematin degradation products. There is, therefore, a need for a stable, effective and well-tolerated haem preparation. We have prepared certain highly soluble haem compounds of which haem arginate has proved to be the most promising. Pure haemin was isolated from HIV and hepatitis B negative human blood. The haem derivatives prepared were screened as substrates for haem oxygenase. Haem arginate and haem lysinate were found to be as good substrates as methaemalbumin. Stock solutions of haem arginate were stable for 2 years at +6 degrees C. After dilution with sterile isotonic saline the haem arginate infusion was clearly more stable than haematin solutions made in the laboratory or prepared by dissolving commercial lyophilized haematin. The antiporphyrogenic effect of haem arginate (even after storage for two years) in 2-allyl-2-isopropylacetamide-induced experimental porphyria of rats was equal to that of freshly prepared haematin. The acute oral toxicity of haem arginate was low compared with the parenterally administered drug, indicating poor oral bioavailability. The acute toxic effects after high intravenous or intraperitoneal doses were directed to the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical and clinical studies on epileptic patients during two phase I trials with the novel anticonvulsant taltrimide.

Taltrimide (2-phthalimidoethanesulphon-N-isopropylamide), a lipophilic derivative of taurine and a potent anticonvulsant in animal studies, was administered in daily doses of 1 and 2 g for 2 weeks with an interval of 2.5 months in 2 phase I clinical trials to 9 drug-resistant epileptic patients. Seizures and EEG were recorded, and routine laboratory studies conducted. Concentrations of antiepileptic drugs in plasma, of amino acids in urine and plasma, and contents of amino acids, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and cyclic nucleotides in the cerebrospinal fluid were determined. Although no clinical or neurophysiological effects were observed, an increase in the cerebrospinal fluid contents of HVA and cyclic nucleotides and changes in the concentrations of antiepileptic drugs and amino acids were found. The concentrations of HVA correlated with those of 5-HIAA and also with those of the main active metabolite of taltrimide. Biochemical changes due to taltrimide treatment resembled only partly those found after taurine treatment.

The effects of haem arginate and haematin upon the allylisopropylacetamide induced experimental porphyria in rats.

Biochemical disorders caused by allylisopropylacetamide in various animal species resemble human acute intermittent porphyria. The antiporphyrogenic efficacy and potency of haem arginate, a new haem compound, were compared with those of haematin in experimental porphyria of rats. Both haem arginate and haematin dose-dependently decreased the urinary excretions of porphyrin precursors. They inhibited significantly the induction of hepatic delta-aminola-evulinic acid synthase. Haem arginate and haematin could restore the activity of haem oxygenase and after higher doses they increased the activity. The dose-effect relationships of the two haem compounds were demonstrated.

Effects of repeated intravenous administration of haem arginate upon hepatic metabolism of foreign compounds in rats and dogs.

Haem arginate is a new haem compound, recently introduced for the treatment of acute hepatic porphyrias. Porphyrias are characterized biochemically by decreased formation of haem due to defects in certain enzyme activities involved in the haem biosynthesis. Haem is essential for cell respiration and oxidative biotransformation. Hepatic drug metabolism, haem biosynthesis and catabolism were investigated after repeated intravenous administration of haem arginate in connection with toxicity studies. The daily doses of haem for rats were 4, 12 and 40 mg kg-1 and for dogs 3 and 9 mg kg-1 for 30 days and for 28 days, respectively. Hepatic microsomes were used in the assay of the following drug metabolizing enzymes: cytochrome P-450 and b5, aminopyrine N-demethylase, ethoxyresorufin O-deethylase and UDP-glucuronyl transferase. The assay of NADPH-cytochrome C-reductase and the enzymes reflecting synthesis and metabolism of haem in the liver (delta-aminolaevulinic acid synthase, delta-aminolaevulinic acid dehydratase, uroporphyrinogen I-synthase, uroporphyrinogen decarboxylase, haem synthase, haem oxygenase and biliverdin reductase) were performed from 20,000 g supernatants. The lowest dose administered to rats and dogs did not cause any significant changes compared to controls in the parameters measured. The highest doses significantly increased the activities of haem oxygenase and uroporphyrinogen I-synthase but decreased concentrations or activities of other enzymes, e.g. cytochrome P-450 and ethoxyresorufin O-deethylase. The results show that it is important to avoid overdosage of haem when restoration of mixed function oxygenase activity is needed.

Effects of taltrimide, an experimental taurine derivative, on photoconvulsive response in epileptic patients.

Taltrimide is a lipophilic taurine derivative with definitive anticonvulsive effects in experimental epilepsy models. In this study, taltrimide was administered for 6 days, and the effects of the treatment on photoconvulsive response in EEG in eight epileptic patients were evaluated. Discharges provoked by intermittent photic stimulation (IPS) were increased by greater than 50% in four patients after taltrimide treatment. Only one patient had reduction of sensitivity. There was only a slight change in discharges after hyperventilation and no change in spontaneous paroxysms. The effects of taltrimide on photosensitivity appear to be rather specific. The study does not reveal anticonvulsive effects of taltrimide in humans.

Fate of haem after parenteral administration of haem arginate to rabbits.

Rabbits were injected either intravenously or intramuscularly with [14C]haem arginate and [59Fe]haem arginate (haem 5 mg kg-1). The main part (80%) of AUCINF of labelled haem was associated with the beta-phase, T1/2 being about 6 h. Only 1% of the haem dose had been taken up by the red blood cells. In contrast, the iron moiety from the haem molecule was effectively utilized. Thirty days post-injection of [59Fe]haem arginate, 40% of the dose after intravenous injection and 60% after intramuscular injection was circulating with the red cells. Radioactivity was shown to concentrate in the liver, where haem is mainly metabolized and eliminated. An accumulation of haem in the adrenals was also evident. Haem itself did not concentrate in the bone marrow, and a negligible amount of radioactivity was recovered from brain, implying a poor penetration of the blood brain barrier.

Barbiturate and ethanol sleeping times and pharmacokinetics of propranolol in mice after intravenous administration of haem arginate.

Haem arginate is a new haem compound recently introduced for treatment of porphyrias. Previously haematin has been reported to increase certain hydroxylase activities in extrahepatic tissues, but even in therapeutic doses it impairs the microsomal foreign substance metabolism in the liver. Haem arginate at a dose equivalent to haem 10 mg/kg (threefold therapeutic dose) did not prolong the hexobarbital sleeping time of mice, 20 mg/kg did prolong the hexobarbital and possibly also the ethanol sleeping time. Haem arginate administered in high doses prior to oral propranolol did not alter the bioavailability of the latter. With regard to drug interactions haem arginate may be safer than haematin.

Pharmacokinetics of intravenously administered haem arginate.

The pharmacokinetics of haem were investigated after intravenous administration of a therapeutic dose of haem arginate (3 mg haem kg-1) to four healthy volunteers and four symptomless porphyric patients. Plasma haem concentrations were measured also during a treatment course of four infusions in six patients with porphyria. Plasma haem concentrations declined monoexponentially over 48 h in both healthy volunteers and porphyric patients, with a mean +/- s.e. mean elimination half-life of 10.8 +/- 0.6 h. Other kinetic parameters were also similar in the two groups, total plasma clearance was 3.7 +/- 0.4 ml min-1 and volume of distribution was 3.37 +/- 0.34 l. In the multiple dose study the elimination half-life increased significantly, from 11.3 +/- 0.4 h to 18.1 +/- 1.4 h over 4 consecutive days. Plasma haemopexin values decreased with time after a single haem arginate dose. The infusion of haem arginate did not cause thrombophlebitis.

Clinical trial with an experimental taurine derivative, taltrimide, in epileptic patients.

The antiepileptic effect, effects on EEG, and tolerability of taltrimide, a new taurine derivative, were studied in this open clinical trial in 27 patients with severe epilepsy resistant to conventional drugs. After the 2-week control phase, taltrimide was given in gradually increasing doses up to 4.0 g/day--this dose used for 12 days. Taltrimide was given over 4 weeks and it was gradually withdrawn over 2 weeks. The frequency of seizures increased statistically significantly during the trial with increasing dose of taltrimide and decreased again in the withdrawal phase of the trial. Of six dropouts, one had status epilepticus, and in two patients increased number or severity of seizures necessitated withdrawal of taltrimide. There were no changes in EEG recordings or in laboratory data for safety evaluation. Taltrimide penetrated well through the blood-brain barrier, with the concentration of its main metabolite, phthalimidoethanesulphonamide, in cerebrospinal fluid, about half that in serum. The concentration of phenytoin increased statistically significantly, and there was a significant decrease in serum carbamazepine concentration during the taltrimide treatment. The anticonvulsive effect of taltrimide observed in animal experiments could not be confirmed in this study; in contrast, the seizures increased statistically significantly during taltrimide treatment. The reason for this remains obscure. The doses used, the significant drug interactions, or the patient material seemingly do not explain totally the noticed increase in seizure frequency. One explanation may be that taltrimide has proconvulsive properties in humans.

Methionine in paracetamol tablets, a tool to reduce paracetamol toxicity.

The analgesic effect, toxicity and kinetics of oral paracetamol were compared with those of paracetamol + l-methionine (5:1). The analgesic effect of paracetamol, studied in the Randall-Selitto test in rats, was not changed by methionine: ED50 was 94.6 mg/kg without methionine and 94.1 mg/kg with it. However, methionine reduced the acute toxicity (LD50) of paracetamol by 50% (p less than 0.05) in non-fasted, fasted and phenobarbital-pretreated mice. In a randomized cross-over study in 10 human volunteers the pharmacokinetics of paracetamol (1,500 mg) was not affected by methionine (300 mg). The absorption of methionine from the combination tablets was rapid, peak concentrations occurred in plasma at 30 min and were 3-4 times higher than after paracetamol tablets not containing methionine. Methionine in products containing paracetamol should increase their safety and be the simplest way to reduce the high mortality in paracetamol overdosage.