Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium after oral administration to man

Summary A method has been developed for the quantitative determination of heptabarbital [5-(1-cyclohepten-1-yl)-5-ethylbarbituric acid] in human plasma after administration of single therapeutic doses of the drug. It involves a single extraction step followed by gas chromatography with alkali flame ionization detection, and the results were linear in the concentration range 0.125 – 5.0 µg/ml plasma. The pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium were studied in a crossover design in 7 healthy volunteers after oral administration of 20 tablets containing 200 mg heptabarbital and hard gelatine capsules containing an equivalent amount of its sodium salt. Heptabarbital concentrations in plasma were determined at regular intervals. The absorption of heptabarbital from the tablets was quite slow and peak level times varied from 1.5 to 4 h. The sodium salt was absorbed more rapidly and peak concentrations occurred between 1/3 and 2 h. In all cases the elimination of heptabarbital could be described by a single first-order process with an average half-life of 7.6 h (range 6.1 – 11.2 h). The half-life of the drug in each individual was about the same in the two trials. The relative bioavailability in each volunteer was estimated by comparing the areas under the plasma concentration curves. The sodium salt had an average bioavailability of 83% relative to the free acid. In some volunteers urinary excretion of unchanged heptabarbital was measured; cumulative excretion amounted to 0.16 – 0.30% of the administered dose. Four volunteers received one tablet each night for eight or ten days, but no accumulation was found. In three volunteers the half-life of the drug prior to and after these experiments did not change, whereas in the other volunteer the half-life decreased from 7.1 to 4.6 h. The possibility of enzyme induction should be considered when heptabarbital is taken regularly. It was concluded that heptabarbital was a suitable drug for the treatment of insomnia, since its half-life was rather short. Heptabarbital sodium may be used for induction of sleep, whereas Medomin^® tablets, i.e. heptabarbital free acid, may be prescribed when the maintenance of sleep is the primary reason for treatment with a hypnotic drug.     

The effect of mercuric chloride on the excretion of two urinary enzymes in the rat

The effect of intravenous injections of HgCl₂ on the renal excretion of alkaline phosphatase (AP) and leucine aminopeptidase (LAP) was investigated in rats. On the first day after Hg enzyme excretion showed a linear rise with the Hg dose from a threshold value of 0.44 mg Hg/kg. On the second day a statistically significant effect was seen already after 0.25 mg Hg/kg. After doses of 0.75 mg/kg or more a decrease of enzyme activity below control values occurred which persisted for more than 4 days.Treatment with 2,3-dimercaptopropansulfonate (DMPS) brought about a normalization of AP excretion. An effect on LAP excretion was observed only with early treatment. The same holds for the effect of DMPS on Hg-induced lethality.The usefulness of a measurement of LAP excretion for estimating the exposure to inorganic mercury is discussed.

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Zusammenfassung Die Wirkung von intravenös verabreichtem HgCl₂ auf die renale Ausscheidung von alkalischer Phosphatase (AP) und Leucinaminopeptidase (LAP) wurde an Ratten untersucht. Am ersten Tag nach Hg-Injektion erfolgte ein Anstieg der Enzymausscheidung, der von einem Schwellenwert von 0.44 mg Hg/kg ausgehend eine lineare Abhängigkeit von der Hg-Dosis aufwies. Am zweiten Tag wurde ein statistisch signifikanter Effekt bereits nach 0.25 mg Hg/kg beobachtet. Nach Dosen von 0.75 mg Hg/kg oder mehr fand ein Abfall der Enzymaktivität unter die Kontrollwerte statt, der mehr als 4 Tage anhielt.Behandlung mit 2,3-Dimercaptopropansulfonat (DMPS) bewirkte eine Normalisierung der AP-Ausscheidung. Eine Wirkung auf die LAP-Exkretion wurde nur bei baldiger Verabreichung von DMPS beobachtet. Das gleiche gilt für den Effekt von DMPS auf die Hg-induzierte Letalität.Die Nützlichkeit einer LAP-Bestimmung im Urin zur Abschätzung einer Hg-Inkorporation wird diskutiert.

     

Cystinuria genotypes predicted from excretion patterns

Genotypes of 17 patients with cystinuria were predicted from data based on excretion rates of the families' obligate carriers. The methodology differed from that used by other investigators as it did not employ intestinal biopsy studies or loading dose measurements. The Type I form was more common than either Type II or Type III and frequently occurred in combination to give compound heterozygous genotypes with the Type III form.     

Renal gluconate excretion after 6-aminonicotinamide

Summary After application of 6-aminonicotinamide, an increasing amount of gluconate was found in the urine. No correlation with the renal excretion of electrolytes could be established.     

Biliary excretion of 64Cu, 65Zn and 203Hg in the rat with liver injury induced by CCl4

In rats the effect of a chronic administration of CCl₄ on the excretion and disstribution of ⁶⁴Cu, ⁶⁵Zn, and ²⁰³Hg was investigated. The biliary excretion of these metals was studied with particular attention. It was found that total excretion of ⁶⁴Cu, ⁶⁵Zn, or ²⁰³Hg from the organism did not change significantly in comparison with the control group, but the ratio of individual excretion pathways did change. The course of excretion curves regarding the bile in exposed animals is prolonged. The histologic examination of the livers revealed a large interindividual variability in the response of the liver tissue to the same CCl₄ exposure. Differences in distribution in the kidneys and livers in exposed and control animals was also found.     

Excretion of Some Drugs in Bovine Tears

Abstract: The excretion of drugs in the tears of cattle was studied, while almost constant plasma concentrations were maintained by continuous intravenous infusion. The examination included both acid and basic drugs. A fairly constant ratio between the concentrations in the tears and the ultrafiltrate of plasma was found for each drug examined. The ratio was not influenced by the rate of secretion or the plasma concentration. For drugs of an acid nature the ratio was less than or equal to 1 (sulphanilamide 0.99, sulphadimidine 0.80, sulphadiazine 0.35, sulphadoxine 0.48, benzylpenicillin 0.004), whereas the ratio for drugs of a basic nature was greater than 1 (penethamate 7.1, trimethoprim 2.2). The above described investigations provide reasons for believing that the passage of the examined drugs from the plasma to the tears may take place by diffusion of the non-protein-bound, unionized fraction.     

Elimination of iodine deficiency disorders in Delhi

Objective: The present study was conducted in year 2002 in NCT of Delhi with the objective to re-assess the prevalence of iodine deficiency disorders.Methods : A total of 7009 children in the age group of 6–11 years were clinically examined for presence of goiter. A total of 991 salt samples were also collected randomly. On the spot casual urine samples were collected from 1395 children.Results : The total goiter prevalence was found to be 6.2 %. The percentage of children with urinary iodine excretion (UIE) of <20.0, 20.0-<50.0, 50.0–99.9 and 100.0 Μg/l and above was 0.8, 1.8, 8.7 and 88.7%, respectively. The median UIE level was 200 Μg/L The assessment of iodine content of salt revealed that only 16% of the families were consuming salt with iodine content less than 5 ppm.Conclusion : The findings of the present study indicated that the population is in a transition phase from iodine deficient (as revealed by Total Goiter Prevalence) to iodine sufficient nutriture (as revealed by median UIE 200 Μg/l). A significant progress has been achieved towards elimination of IDD from NCT of Delhi.     

The impact of dietary oxalate on kidney stone formation

The role of dietary oxalate in calcium oxalate kidney stone formation remains unclear. However, due to the risk for stone disease that is associated with a low calcium intake, dietary oxalate is believed to be an important contributing factor. In this review, we have examined the available evidence related to the ingestion of dietary oxalate, its intestinal absorption, and its handling by the kidney. The only difference identified to date between normal individuals and those who form stones is in the intestinal absorption of oxalate. Differences in dietary oxalate intake and in renal oxalate excretion are two other parameters that are likely to receive close scrutiny in the near future, because the research tools required for these investigations are now available. Such research, together with more extensive examinations of intestinal oxalate absorption, should help clarify the role of dietary oxalate in stone formation.     

Urinary acidification in extremely low birth weight infants

Premature infants often present metabolic acidosis without protein load in the early neonatal period, around days 4–6. In order to elucidate the cause of acidosis, we investigated urinary acidification of infants in the early neonatal period.

Urine pH, fractional excretion of HCO₃⁻ (FEHCO₃), excretion of HCO₃⁻ and NH₄⁺ of the appropriate-for-date infants were measured on days 0–2 and on days 4–6 of life.

Extremely low birth weight (ELBW) infants showed higher urine pH than more than 1500 g birth weight infants. FEHCO₃ and HCO₃⁻ excretion were of high values in ELBW infants on days 0–2, but decreased on days 4–6. Urine NH₄⁺ excretion rate was lower in ELBW infants than in birth weight more than 1000 g on days 0–2 of life and still remained at a low rate on days 4–6.

These data indicated that insufficiency of NH₄⁺ excretion is the main cause for metabolic acidosis of ELBW infants in the early neonatal period.