Pharmaceutical Research

Stahl, Egon; Quirin, Karl

doi: 10.1023/A:1016313111693pmid: 24277327

An overview of the solvent power of dense gases is given. The properties of these novel solvents are described and the specific advantages of carbon dioxide discussed. New qualitative and quantitative procedures for the rapid determination of solubilities are described for several interesting classes of natural substances. These include fatty oils, steroids, alkaloids, flavor and aroma substances, which documents the versatility of the new extraction procedure in many practical applications.

Ullman, Buddy

doi: 10.1023/A:1016365128531pmid: 24277328

The pyrazolopyrimidines are purine analogs that are cytotoxic toward and metabolized by several genera of parasitic protozoa, including the Leishmania and the Trypanosoma. Examples of pyrazolopyrimidines that are selectively metabolized by these parasites include allopurinol, allopurinol riboside, 4-thiopurinol, 4-thiopurinol riboside, and formycin B. These pathogenic protozoa are capable of efficient conversion of the pyrazolopyrimidines to the nucleotide level. The pyrazolopyrimidine metabolites which are isomers of inosine monophosphate are subsequently aminated and incorporated as the adenylate analog into RNA. Mammalian cells are incapable of these metabolic transformations. The sulfur containing pyrazolopyrimidines, however, are neither aminated nor incorporated into nucleic acid. The selective metabolism of the pyrazolopyrimidines by the intracellular metabolic machinery of the parasites of the Trypanosomatidae family offers a rational approach to the chemotherapy of the diseases caused by these pathogenic hemoflagellates.

Couet, William; Eriksson, Ulf; Tozer, Thomas; Tuck, L.; Wesbey, George; Nitecki, Danute; Brasch, Robert

doi: 10.1023/A:1016317212601pmid: 24277329

Paramagnetic nitroxyl-containing compounds have been useful as contrast agents in magnetic resonance imaging (MRI) experiments in animals. Preliminary information on the metabolic fate, pharmacokinetic behavior, stability in tissues, and chemical reduction of two prototypic nitroxides, PCA and TES, is presented. In the dog TES was eliminated more rapidly than PCA. More than 80 % of the dose of both nitroxides was recovered in urine within 6 hours. Nitroxides were reduced in vivo to their corresponding hydroxylamines. No other metabolite was observed. Measured reducing activity in tissue homogenates was greater in liver or kidney than in brain, lung or heart. In each tissue PCA was more stable than TES. PCA was also more resistant to reduction by ascorbic acid at physiologic pH. These preliminary results favor the use of PCA, a pyrrolidinyl nitroxide, over TES, a piperidinyl nitroxide, for MRI contrast enhancement.

Grevel, Joachim; Thomas, Jeff; Richards, Mark; Sadée, Wolfgang

doi: 10.1023/A:1016369229440pmid: 24277330

A sensitive radioreceptor assay (RRA) to determine the serum concentrations of fentanyl, pentazocine and morphine was developed on the basis of the drug's competition with a labeled tracer (3H-naloxone) for the membrane bound opioid receptor in rat brain homogenates. The binding data were computer-fitted to a standard curve by means of nonlinear least square regression. Sensitivity of the assay applied directly to serum samples without extraction was limited to approximately 3, 5 and 25 ng/ml for fentanyl, morphine and pentazocine, respectively, because of endogenous plasma constituents that interfere with the opioid receptor binding. With the use of petrol-ether extraction the sensitivity was improved to 0.3 ng/ml fentanyl and 3 ng/ml pentazocine (0.3 ml serum samples). No RRA-active metabolites were detectable after HPLC separation of serum from a patient treated with fentanyl. The plasma concentration time course of fentanyl in a patient, measured by RRA, was similar to that obtained by a radioimmunoassay (RIA). The RRA represents a general procedure for the detection of clinically used opioid analgesics and their active metabolites.

Heptner, Wolfgang; Badian, Mario; Baudner, Siegfried; Hellstern, Christa; Irmisch, Robert; Rupp, Werner; Weimer, Kurt; Wissmann, Hans

doi: 10.1023/A:1016321313510pmid: 24277331

An antiserum was prepared for the determination of glibenclamide and for the estimation of other commercially available sulfonylureas. Rabbits were immunized with a glibenclamide-BSA conjugate. Tritiated glibenclamide was used as the tracer. The assay was performed in the presence of 8-anilinonaphthalenesulfonic acid to displace glibenclamide bound to serum protein, and free and antibody bound tracer were separated by dextran-coated charcoal. For glibenclamide determination in serum and plasma the limit of detection was 3 ng/ml. Sensitivity calculated for the whole determination range was 102 cpm for a 10 % concentration difference. Specificity studies showed a cross-reaction of less than 0.1 % for glibenclamide metabolite M1 and 9 % for metabolite M2. Other sulfonylurea drugs display cross-reactivities from 0.1% (chlorpropamide) to 190% (gliquidone). Both intra-assay and inter-assay imprecision were below 10 %. Accuracy was established by comparison of the present method with HPLC. The assay was applied to the specific determination of glibenclamide in clinical trials and for diagnosing factitious hypoglycemia caused by sulfonylureas.

Kimura, Toshikiro; Higaki, Kazutaka; Sezaki, Hitoshi

doi: 10.1023/A:1016373330348pmid: 24277332

Intestinal absorption of liposomally-entrapped drugs was investigated for egg yolk phosphatidylcholine-cholesterol (2:1 by molar ratio) liposomes (EggPC liposome) and distearoylphosphatidylcholine-cholesterol (2:1) liposomes (DSPC liposome). The release of carboxyfluorescein, an aqueous phase marker, induced by the presence of everted rat intestine was 40 % and 6 % in one hour from DSPC liposomes and EggPC liposomes, respectively, and it is suggested that EggPC liposomes are more stable in the intestinal lumen. The transport of a liposomally-entrapped drug was examined with fluoresceinisothiocyanate-conjugated dextran (FITC-D) as a model drug that has a small mucosal-to-serosal clearance because of its high average molecular weight (64200). The clearance of FITC-D entrapped in DSPC liposomes was largely reduced and could be accounted for by the clearance of the extraliposomal FITC-D concentration in the preparation. On the other hand, the calculated clearance of EggPC liposome-associated FITC-D was similar to or even higher than that of free FITC-D. The serosal appearance of the EggPC liposome-associated drug was inhibited by colchicine, cytochalasin B, and iodoacetate, suggesting that the liposome was incorporated into the epithelial cells by endocytosis. However, the observation that a lipid phase marker, 14C-dipalmitoylphosphatidylcholine, failed to be transported into the serosal fluid indicates the absence of the penetration by an intact liposomal form.

Derendorf, Hartmut; Drehsen, Gertrude; Rohdewald, Peter

doi: 10.1023/A:1016325414419pmid: 24277333

The time courses of analgesic activity of 4 different tablets containing different amounts of antipyrine were determined in 14 volunteers using electrical tooth pulp stimulation to elicit pain. Drug action was monitored by following somatosensory evoked potentials obtained from electroencephalographic measurements as well as pain rating and pain threshold determination. The results were compared with data obtained after administration of 1000 mg acetaminophen and two different doses of aspirin (500 and 1000 mg). At the same time drug concentration in saliva of the same volunteers was analyzed by quantitative in situ thin-layer-chromatography to investigate the pharmacokinetics. Furthermore, the in vitro drug release from the different tablets was studied with a continuous flow cell model. Antipyrine produced reliable analgesic activity. The onset of action was significantly faster than after administration of the same dose of aspirin, and the effect lasted longer than after intake of the same dose of acetaminophen. Comparison of the drug action and drug level in the body showed an excellent correlation between pharmacodynamics and pharmacokinetics. The study confirms our earlier findings on the value of somatosensory evoked potentials as a method to investigate the pharmacodynamics of weak analgesics in humans. The results also suggest to reconsider the use of antipyrine as an over-the-counter analgesic.

Bhattacharya, Salil; Rao, Patchala; Bhattacharya, Dipankar

doi: 10.1023/A:1016377431257pmid: 24277334

Prostaglandin E1 (PGE1) produced dose-related catalepsy in rats when administered intracerebroventricularly. PGE1 induced catalepsy was significantly inhibited after pretreatment with pharmacological agents known to attenuate central serotonergic and cholinergic activity. It was also inhibited by PGF2α and naloxone. On the contrary, treatments enhancing central dopaminergic activity also reduced the cataleptic effect of PGE1. The results suggest that PGE1 induces catalepsy in rats by modulating activity of central neurotransmitters.

Rocci, Mario; Mojaverian, Parviz; Saccar, Consuelo

doi: 10.1023/A:1016329515327pmid: 24277335

The effects of morphine on the single dose pharmacokinetics of theophylline were examined in two groups (6 rats/group) of male Sprague-Dawley rats after the administration of theophylline (6.25 mg/kg) alone and in conjunction with a 5 mg /kg I.V. dose of morphine sulfate. Concomitant morphine administration resulted in a 55 % reduction in theophylline clearance (0.14 ± 0.04 vs. 0.31 ± 0.061 · h−1 kg−1; p. < 0.0005). The reduction in theophylline clearance with morphine administration was accompanied by a significant prolongation in theophylline half-life (3.5 ± 1.5 vs. 1.4 ± 0.35 h; p < 0.02). No changes in the volume of distribution of theophylline occurred with co-administration of morphine. The mechanism of this pharmacokinetic interaction may be partially related to competition between theophylline and morphine for enzymes which metabolize these compounds.

Römer, Klaus; Freundt, Klaus; Alanis, Oscar; de Torres, Graciela

doi: 10.1023/A:1016381532166pmid: 24277336

Adult female Sprague-Dawley rats received ethanol (2 g/kg b.w., i.p.) 18 hours after pretreatment with the betalactam-antibiotics cefamandole (CMD) or cefoperazone (CPZ) (1 mmol/kg b.w. each, i.p.). The blood ethanol concentrations, determined repeatedly within 4 hours by head space GC, were increasingly elevated after CMD or CPZ up to twice the respective control values. The possible clinical and forensic significance of these findings for the therapeutic use of CMD or CPZ is pointed out.