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H Jung

Publications and source records attributed to H Jung.

At least 73 records · Page 4Linked to original sources
PubMed1998

Absorption studies of albendazole and some physicochemical properties of the drug and its metabolite albendazole sulphoxide.

In several studies of patients with neurocysticercosis under treatment with albendazole the pharmacokinetic data were difficult to interpret, probably because of slow and erratic drug dissolution response and absorption problems in-vivo. Because there is no information available about the physicochemical properties of the drug, the aim of this work was to explain this erratic behaviour by fully characterizing the solution behaviour of the drug and its metabolite. To accomplish this, the physicochemical properties, pKa and solubility, and in-vitro plasma binding of albendazole and its main metabolite, albendazole sulphoxide, were studied by conventional methods. The intestinal and gastric absorption and dissolution behaviour of albendazole were also studied. The solubility of both compounds is very low. Both are amphoteric molecules with two ionization steps, with pKa values of 10.26 and 2.80 for albendazole and 9.79 and 0.20 for albendazole sulphoxide; low pKa values were obtained by performing linear free energy relationship calculations. On the other hand, protein binding studies showed that albendazole is 89-92% bound to plasma proteins whereas for albendazole sulphoxide the figure is 62-67%. This metabolite is bound by albumin and to alpha1-glycoprotein. Absorption of albendazole occurs along the gastrointestinal tract and is limited by its solubility. Good dissolution profiles were observed when 0.1 M HCl was used as dissolution medium. The results show that 0.1 M HCl enables discrimination between the drug-release characteristics of different products.

Albendazole↗
PubMed1998

Pharmacokinetic interaction in rabbits between a new anticonvulsant, DL-3-hydroxy-3-ethyl-3-phenylpropionamide, and phenytoin.

The effect of phenytoin on the disposition of DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) has been studied in New Zealand white rabbits. Plasma HEPP levels decreased when the drug was administered with phenytoin. The area under the plasma concentration-time curve was reduced by 56.49% (from 43.23+/-7.0 to 18.81+/-2.03 microg h mL(-1)), the elimination half-life was also significantly (P<0.01) reduced (from 2.68+/-0.35 to 1.04+/-0.07 h) and the clearance was increased (from 0.35 to 0.81 L h(-1) kg(-1)). In-vitro protein binding to bovine serum albumin (BSA) and plasma was evaluated by equilibrium dialysis. Plasma protein binding was low (between 33.69 and 37.43% at concentrations ranging from 6.25 to 100 microg mL(-1)). The compound binds preferentially to albumin with an association constant (Ka) of 3.81 x 10(3) M(-1) at 37 degrees C. The results suggest a pharmacokinetic interaction between phenytoin and HEPP, probably on the drug-metabolizing enzyme system in the liver.

Animals↗
PubMed1998

Pharmacokinetic optimisation of the treatment of neurocysticercosis.

Neurocysticercosis is the most important parasitic infection of the nervous system. It is common in communities living in conditions with poor hygiene. Until the last 2 decades, there was no specific pharmacological treatment: surgery and corticosteroids were the only medical alternatives. The recent introduction of anticysticercal drugs, an isoquinoline (praziquantel) and a benzimidazole (albendazole), has dramatically changed the medical management of neurocysticercosis. Praziquantel is taken orally and undergoes extensive first pass hepatic biotransformation. Peak concentration in serum is reached after 1 to 2 hours and the elimination half-life is between 1 and 3 hours. Praziquantel permeates the blood-brain barrier, thus explaining its effectiveness on parenchymal brain cysticercosis. Plasma concentrations of the drug are increased when a high carbohydrate diet is administered. Cimetidine also increases the plasma concentration of praziquantel by inhibition of cytochrome P450. Bioavailability of the drug is markedly reduced when given jointly with antiepileptics or corticosteroids, specially carbamazepine, phenytoin or dexamethasone. The current schedule for neurocysticercosis treatment lasts 2 weeks at daily doses of 50 mg/kg. Recently, a new therapeutic scheme has been proposed that considers the pharmacokinetics of the drug. This regime lasts only 1 day and includes 3 dosages of 25 mg/kg at 2-hour intervals. This increases the time that the parasite is exposed to high drug concentrations. This therapeutic scheme has produced similar results to longer schemes, with the additional advantages of cost, length of usual treatments and reduction in total dose received (being one-tenth of the total dosage). Albendazole is considered by many as the drug of choice for treatment of neurocysticercosis. It is given orally and is rapidly and extensively metabolised to albendazole sulfoxide (ALBSO), which is considered to be the metabolite directly or indirectly responsible for both toxicity and efficacy outside the gastrointestinal tract. Concentrations of ALBSO are highly variable between individuals and it has a half-life of between 6 and 15 hours. It also crosses the blood-brain barrier. In patients with extrahepatic obstruction, the elimination process is prolonged and plasma concentration is increased. Fatty meals improve absorption. Concomitant administration of albendazole with dexamethasone or with praziquantel increases plasma concentration of ALBSO. Albendazole is administered in an 8 day course of 15 mg/kg per day in 2 divided doses 12 hours apart. This scheme, based on drug pharmacokinetics, has proven to be highly effective. Inflammation is a common accompaniment of neurocysticercosis; in many cases it is the aetiopathogen responsible for histological damage. Corticosteroid therapy is useful for preventing further tissue injury. Long term corticosteroid therapy can be accomplished with 50 mg of oral prednisone 3 times a week. Acute corticosteroid therapy includes brief courses with high dosages of intramuscular dexamethasone or intravenous methylprednisolone. Clinical decisions on cysticidal and anti-inflammatory treatments must be made with the information gathered by neuroimaging studies, either computed tomography or magnetic resonance, and by the analysis of cerebrospinal fluid.

Absorption↗
PubMed1998

[Mammography and radiation risk].

Breast cancer is the most frequent malignant neoplasia among women in Germany. The use of mammography as the most relevant diagnostic procedure has increased rapidly over the last decade. Radiation risks associated with mammography may be estimated from the results of numerous epidemiological studies providing risk coefficients for breast cancer in relation to age at exposure. Various calculations can be performed using the risk coefficients. For instance, a single mammography examination (bilateral, two views of each breast) of a women aged 45 may enhance the risk of developing breast cancer during her lifetime numerically from about 12% to 12.0036%. This increase in risk is lower by a factor of 3,300 as compared to the risk of developing breast cancer in the absence of radiation exposure. At the age of 40 or more, the benefit of mammography exceeds the radiation risk by a factor of about 100. At higher ages this factor increases further. Finally, the dualism of individual risk and collective risk is considered. It is shown that the individual risk of a patient, even after multiple mammography examinations, is vanishingly small. Nevertheless, the basic principle of minimising radiation exposure must be followed to keep the collective risk in the total population as low as reasonably achievable.

Adult↗
PubMed1997

Metabolism of isomeric nitrobenzo[a]pyrenes leading to DNA adducts and mutagenesis.

We have been interested in determining the structural and electronic features that may be useful in predicting the mutagenic activity of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs). We have previously found that a correlation between structural and electronic features and direct-acting mutagenicity in Salmonella typhimurium cannot be made using nitro-PAHs with different molecular size. In this study, a series of structurally related nitro-PAHs, the environmental contaminants 1-, 3-, and 6-nitrobenzo[alpha]pyrene (NBaP) and their derivatives, was used to determine structure-activity relationships. It was found that isomeric NBaPs are activated to DNA damaging and mutagenic derivatives by nitroreduction, ring-oxidation, or by a combination of these two pathways. A general finding was that NBaPs and derivatives with their nitro substituent oriented perpendicular to the aromatic system exhibit either very weak or no direct-acting mutagenicity in S. typhimurium strains TA98 and TA100. In this paper, we also discuss the effect of the location of the nitro group on the metabolism and the mutagenicity of NBaPs and the effect of oxygen-containing functional groups on the mutagenicity of NBaP derivatives. These findings provide a useful molecular basis for interpreting and predicting the direct-acting mutagenicity of nitro-PAHs.

Animals↗
PubMed1997

Aspartate 55 in the Na+/proline permease of Escherichia coli is essential for Na+-coupled proline uptake.

Four acidic residues in the N-terminal domain of Na+/proline permease of Escherichia coli (Asp33, Asp34, and Asp55 in putative loop 2, Glu75 in putative transmembrane domain II) were individually replaced with neutral or charged amino acid residues. Replacement of Glu75, the only residue in the permease presumed to be in the middle of a transmembrane domain, Asp33, or Asp34 had little or no influence on the kinetics of Na+-coupled proline transport. In contrast, removal of the carboxylate at position 55 (Asp55 --> Asn or Asp55 --> Cys permease) impaired proline uptake completely while lengthening of the side chain at this position by one methylene group (Asp55 --> Glu permease) allowed transport at a reduced initial rate. Importantly, all permease molecules were present in the membrane at concentrations comparable to the wild-type protein. Kinetic analysis of Na+-coupled proline transport catalyzed by Asp55 --> Glu permease revealed a 5-fold increase of the K(m) for proline and a 30-fold decrease of the V(max) compared to wild-type. Remarkably, replacement of Asp55 by Glu led to a 50-fold decrease of the apparent affinity of the permease for Na+. Furthermore, replacement of Asp55 with Cys or Asn blocked proline-induced Na+ uptake whereas significant Na+ transport was observed with Asp55 --> Glu permease. In addition, transport of proline down its concentration gradient was not detectable with deenergized cells containing Asp55 --> Glu permease at low Na+ concentrations. However, downhill transport activity was observed in the presence of high Na+ concentrations. Replacement of Asp55 with Asn or Cys impaired downhill transport under all conditions tested. The observations demonstrate that a carboxylate at position 55 of proline permease is essential for Na+-coupled proline transport. It is suggested that Asp55 may be involved in binding of the coupling ion.

Amino Acid Sequence↗
PubMed1997

The distribution of 10-hydroxy carbazepine in blood compartments.

The distribution of 10-hydroxy carbazepine (MHD), the main metabolite of oxcarbazepine (OXC), was investigated in plasma and red cells. After the oral administration of 600mg of OXC to nine healthy volunteers, blood samples were withdrawn for the next 56h and packed red cells were separated from plasma by centrifugation. Also, in vitro studies of plasma binding of MHD were carried out by a dialysis technique. Results showed that the in vitro protein binding was low. The mean bound concentration ranged from 37 to 40%; however, an affinity of MHD to red corpuscles was found. These observations indicate that MHD red blood cell concentrations together with plasma measurements could be useful in cases of inefficacy or toxicity in order to make the appropriate drug adjustments.

Administration, Oral↗
PubMed1997

The influence of coffee with milk and tea with milk on the bioavailability of tetracycline.

The effect of milk added to coffee or black tea on the bioavailability of tetracycline was evaluated in 12 healthy volunteers according to a crossover design. Results showed that even a small volume of milk containing extremely small amounts of calcium severely impair the absorption of the drug, so that the presence of this metal ion should be carefully controlled in order to avoid decreasing the available tetracycline.

Adult↗
PubMed1997

Involvement of gamma amino butyric acid (GABA) in the postnatal function of the GnRH pulse generator as determined on the basis of GnRH and GnRH-receptor gene expression in the hypothalamus and the pituitary.

In many species the GnRH pulse generator functions early postnatally to become arrested during infancy. In rats highly variable LH levels in 15-day-old animals are suggestive that LH is being released by the pituitary in pulses whereas between day 20 after birth and puberty LH levels are low indicating that the GnRH pulse generator is arrested. In the present study we show on the basis of consecutively withdrawn blood samples in 15-day-old animals that LH pulses are indeed present at that age. The proper function of GnRH receptors in the pituitary is crucially dependent on pulsatile GnRH release from the hypothalamus. In addition, GnRH receptors have been demonstrated in the medial preoptic area and in the mediobasal hypothalamus of adult rats. In 15-day-old animals the functional GnRH pulse generator results in upregulated GnRH receptor gene expression as demonstrated by quantitative RT-PCR. It is not known what neural mechanisms are involved in turning the GnRH pulse generator off during infancy and a GABAergic brake has been discussed. Indeed, when 30-day-old animals were injected with the GABA-A receptor blocking drug bicuculline, this resulted in increased serum LH levels indicating that a tonic GABAergic inhibition is indeed operative at this age.

Aging↗
PubMed1997

Clinical pharmacokinetics of albendazole in children with neurocysticercosis.

The pharmacokinetics of albendazole sulphoxide, the main metabolite of albendazole, were studied in eight children with brain cysticercosis. Albendazole was given as a single oral dose of 15 mg per kg body weight (Zentel suspension; Smith Kline & Beecham, Philadelphia, PA). Blood samples were taken during 24 h and analyzed by high performance liquid chromatography. Plasma levels showed great interindividual variation. Maximum plasma levels for albendazole sulphoxide ranged from 0.2-1.0 microg/mL. A double peak was found in four children. The half-life for albendazole sulphoxide was from 2.3-8.3 hours and mean residence time values were from 5. 1-13.6 hours. These values are shorter than those found in adults. The results suggest that when treating children with neurocysticercosis, albendazole should be administered three times a day rather than twice daily as is currently done in Mexico.

Adolescent↗
PubMed1997

Pharmacokinetic study of praziquantel administered alone and in combination with cimetidine in a single-day therapeutic regimen.

A brief therapeutic regimen of praziquantel, reduced to a single day, has been effective for treatment of neurocysticercosis. To study its pharmacokinetic characteristics, levels of praziquantel in plasma were determined for eight healthy volunteers after the administration of three oral doses of 25 mg/kg of body weight given at 2-h intervals, alone and with the simultaneous administration of cimetidine. Each volunteer received both regimens in a randomized crossover design. Blood samples were taken during a period of 12 h, and praziquantel concentration was measured by high-performance liquid chromatography. Levels of praziquantel in plasma remained above 300 ng/ml during a period of 12 h; they increased 100% when cimetidine was jointly administered. Compared with other regimens, the high levels obtained and the longer duration of action seem to be advantageous in prolonging the exposure of the parasites to the drug and support previous clinical experience showing that the treatment of neurocysticercosis with praziquantel can be reduced from 2 weeks to 1 day with the drug still retaining its cysticidal properties. Moreover, simultaneous administration of praziquantel and cimetidine could improve further the efficacy of the single-day therapy for cysticercosis and other parasitic diseases, such as schistosomiasis.

Administration, Oral↗
PubMed1996

Ser57 in the Na+/proline permease of Escherichia coli is critical for high-affinity proline uptake.

Ser57 in the Na+/proline permease of Escherichia coli has been replaced with alanine, cysteine, glycine, or threonine, and properties of the corresponding putP mutants have been analyzed. Although Ser57 is not essential for activity, the amino acid side chain at this position is critical for proline uptake. Thus, alanine, cysteine, glycine, or threonine in place of Ser57 reduces the initial rate of proline transport under standard conditions to less than 10% of the wild-type value. In addition, substitution of Ser57 in the Na+/proline permease reduces the sensitivity of E. coli cells to the toxic proline analogs L-azetidine-2-carboxylate and 3.4-dehydro-D.L-proline. Replacement of Ser57 with alanine or cysteine results in apparent affinities for proline that are reduced by more than two orders of magnitude, and permeases with threonine and glycine in place of Ser57 yield apparent affinities reduced by a factor of 60 and 18 respectively, relative to wild-type. In contrast, all of the Ser57 replacements analyzed cause only small changes in Vmax values. All permease molecules containing Ser57 substitutions are inserted into the membrane in amounts comparable to the wild-type protein as shown by immunoblot analysis. These results indicate that alterations of proline transport and sensitivity to toxic proline analogs have to be attributed primarily to defects in substrate binding. It is suggested that the serine residue at position 57 of the permease is located within the substrate-binding domain of the protein.

Amino Acid Sequence↗
PubMed1996

Conformation of a beta-adrenoceptor-derived signal transducing peptide as inferred by circular dichroism and 1H NMR spectroscopy.

The peptide T345-359 representing the fourth intracellular loop of the avian beta-adrenoceptor has been shown to strongly inhibit receptor-mediated adenylate cyclase activity [Münch, G., Dees, C., Hekman, M., & Palm, D. (1991) Eur. J. Biochem. 198, 357-364]. Circular dichroism and two-dimensional 1H NMR techniques were used to investigate the three-dimensional structure of the peptide in trifluoroethanol, phospholipid micelles, and small unilamellar phospholipid vesicles. The prepared vesicles were tested for size distribution and stability by using electron microscopy, photon correlation spectroscopy, and 31P NMR spectroscopy. The peptide T345-359 adopted a predominantly alpha-helical conformation in either trifluoroethanol or phospholipid micelles and vesicles. No structural differences were found for the conformation of the peptide in the presence of phospholipid micelles or vesicles, respectively, using 2D 1H NMR techniques, suggesting a unique conformation of T345-359 when associated with model membranes. A computer-aided model of the micelle-associated peptide was derived. The relevance of the 3D structure of the intracellular loops of receptors to communicate with the G protein in the signal transduction cascade is discussed.

Amino Acid Sequence↗
PubMed1996

Hip-simulator ranking of polyethylene wear: comparisons between ceramic heads of different sizes.

We carried out simulator studies on ceramic-polyethylene total-hip combinations to determine the volumetric wear-rates of 22 mm, 26 mm and 28 mm femoral-head sizes. Bovine-serum lubrication and 2 kN peak sinusoidal load-profile were used with polyethylene (UHMWPE) cups. Wear was assessed by gravimetric technique. Precision (9%) was ensured by the use of multiple specimens, multiple wear-events, and the linear-regression method of estimating the average wear trend, thereby reducing the inherent, unpredictable nature of each wear-event. Volumetric wear-rates for polyethylene averaged 23 mm3 per 10(6) cycles for the 22 mm ceramic head and up to 32 mm3 per 10(6) cycles for the 28 mm head. The difference between 22 mm and the larger head-sizes was significant. This may well be the first laboratory confirmation of Charnley's original clinical Low-Friction Arthroplasty concept with regard to wear rate. The wear penalty increased linearly at the rate of 6% to 9% per mm of diameter increase.

Ceramics↗