An LC-MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model.

The 8-aminoquinoline drug primaquine (PQ) is currently the only drug in use against the persistent malaria caused by the hypnozoite-forming strains P. vivax and P. ovale. However, despite decades of research, its complete metabolic profile is still poorly understood. In the present study, the metabolism of PQ was evaluated by incubating the drug with pooled human hepatocytes cultured in vitro as well as with recombinant cytochrome P450 (CYP) iso- enzymes, monoamine oxidases (MAO), and flavin-containing monooxygenases (FMO). Targeted LC-MS/MS analysis of hepatocyte incubations using chemical inhibitors indicated that PQ was predominantly metabolized by CYPs 3A4, 1A2 and 2D6, MAO-A, -B and FMO-3. Confirmation of these results was sought by incubation of PQ with the corresponding recombinant enzymes. Small amounts of carboxyprimaquine (CPQ), the major observed PQ metabolite in vivo, were detected in recombinant MAO-A incubations along with another peak at m/z 261, and no significant formation of CPQ with any other recombinant enzymes was observed. Incubations with all recombinant enzymes identified as potentially active towards PQ from the hepatocyte-based assay resulted in significant parent loss over the course of 1 h. These results suggest that several enzymes, including CYPs in combination with FMOs and MAOs, play a role in the overall metabolism of PQ and indicate a major role for MAO-A. Future studies to elucidate the potential role in cytotoxicity and/or efficacy of the PQ metabolite observed at m/z 261, as observed in MAO-A isoenzyme studies, are needed.

Sonographically guided percutaneous biopsy of gastrointestinal tract lesions.

OBJECTIVE: Our objective was to evaluate the role and safety of sonographically guided percutaneous biopsy in the diagnosis of digestive tract lesions when the lesions are not suitable to biopsy by endoscopy and safely reachable by sonography. MATERIALS AND METHODS: We performed 42 biopsies in 41 patients (age range, 14-81 years; mean age, 57.5 years). We performed biopsies with real-time sonographic guidance using graded compression, with a 3.5-5-MHz microconvex transducer. In 39 biopsies, core specimens were obtained with an 18-gauge automatic needle gun; fine-needle aspiration biopsy was obtained in 28 patients with a 22-gauge needle and in the other four patients with a 21-gauge needle. In the remaining three patients, a coaxial technique with 20- and 22-gauge needles for cytology was used. RESULTS: In 40 (95.2%) of 42 core biopsies performed, a specific diagnosis was obtained. A positive diagnosis was obtained in 16 (45.7%) of 35 fine-needle aspirations. The lesions were located from the pharynx to the sigmoid colon. Twenty-eight patients had malignant lesions, and 13 had benign lesions. Only one serious complication, bile peritonitis, was observed. CONCLUSION: Percutaneous biopsy with sonographic guidance can be used safely and efficiently to diagnose digestive tract lesions that can be visualized on sonography and are not accessible endoscopically.

Reflexiones sobre la pauta con heparinas de bajo peso molecular más idónea para la profilaxis antitrombótica en artroplastia de cadera y rodilla / Considerations about the optimal regimen with low-molecular weight heparins for the antithrombotic prophylaxis in hyp and knee arthroplasty

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Radiografía de tórax

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Interrelación entre el tiempo de tromboplastina parcial activada (TTPA), la generación de trombina y el sistema antigénico ABO / Interrelation between activated partial thromboplastin time (APTT), thrombin generation and ABO antigenic system

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Hipertiroidismo e hipercalcemia asociados al tratamiento con litio

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Carcinomatosis meníngea con celularidad y bioquímica normales en líquido cefalorraquídeo

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[Echography-guided percutaneous biopsy of pleural lesions and effusions]. / Biopsia percutánea de lesiones y derrames pleurales dirigida por ecografía.

Our experience in the use of ultrasonic echography (UE) is exposed as a guide for directing small lesions and pleural effusions percutaneous lesions with an unknown grounds. We have done pleural percutaneous biopsy using UE as guide in 45 patients. The needle diameter ranges between 17 and 19.5 G. Lesions were benign for 16 patients and malignant for 29. The right result was obtained in 93% of the cases. There were not complications. We conclude that echography-directed pleural biopsy presents an excellent diagnostic profitability, it improves the results obtained with blind biopsy with Cope's needle and it must precede thoracoscopy by means of its less aggressiveness.

[Persistence of hypercoagulability state after hip and knee arthroplasty: what is the optimal duration of antithrombotic guidelines in this surgery?]. / Persistencia del estado de hipercoagulabilidad tras artroplastia de cadera y rodilla: cuál debe ser la duración óptima de las pautas antitrombóticas en esta cirugía?

Among 79 patients candidates to hip (53) and knee (26) replacement an evaluation was made of the influence of a two-week program with LMWH on the evolution of hypercoagulability markers: D-D, TAT, and F1 + 2. Measurements were performed by ELISA preoperatively and on days 1, 7 and about 45 postoperatively; in the latter, two extraction intervals were considered: < or = 45 days and > 45 days. With both surgical modalities, D-D and F1 + 2 peaked at 7th day postoperatively, whereas TAT peaked on day 1. Among D-D and F1 + 2 values quantitated on day 7th and the extraction interval < or = 45 days, no significant differences were obtained (Z < 2.64). The hypercoagulative chronicity exhibited by D-D and F1 + 2 during the first month and a half after this surgery, might require in some cases a more prolonged thromboprophylaxis.

[Cacchi Ricci disease. Report of a case]. / Enfermedad de Cacchi Ricci. A propósito de un caso.

OBJECTIVE: To present a case of medullary sponge kidney (Cacchi-Ricci disease) with special reference to the radiologid findings that permit early diagnosis of this rare condition. METHODS: The most relevant clinical features and radiological findings in a patient with Cacchi-Ricci disease are described. RESULTS/CONCLUSIONS: Medullaty sponge kidney, tubular ectasia or Cacchi-Ricci disease is a congenital renal medullary cystic disease that is asymptomatic in most of the cases, but can also present with hematuria, urinary infection or renal colic, with the characteristic spony, porous appearance of the dilated collecting tubules and small calculi in the papilla or renal pyramids on the IVP and, if numerous, also on US. This condition should be distinguished from nephrocalcinosis.

Characterization of solid liver lesions with color and pulsed Doppler imaging.

BACKGROUND: To assess the usefulness of color Doppler and duplex sonography in the characterization of solid liver lesions. METHODS: We performed color Doppler and duplex sonography on 106 solid hepatic lesions. With color Doppler, we evaluated the aspect and distribution of tumoral vessels. The pulsed Doppler parameters considered were only those showing the highest systolic peak velocity values. RESULTS: Intratumoral color and pulsed Doppler signals were obtained in 81% (59/73) of malignant tumors (p < 0. 0001) but only in 18% (6/33) of benign tumors. Ninety-six percent (45/47) of the lesions with arterial intratumoral and peritumoral signals were malignant, whereas 4% were benign (p < 0.0001). Only eight (11%) malignant lesions had intratumoral venous signal vis-a-vis 23 (70%) benign. Twelve cases showing intratumoral venous Doppler signal as a single finding were benign. No statistically significant differences were observed in the quantitative parameters recorded by pulsed Doppler (Student t test, p < 0.05), there having been a clear overlapping in the values obtained in benign and malignant lesions. CONCLUSIONS: (a) The type of signal (arterial or venous) and its distribution detected by color and pulsed Doppler is more helpful than the assessment of the spectral quantitative parameters obtained by pulsed Doppler. (b) The presence of intratumoral venous flow remarkably suggests benignancy. (c) The presence of both intra- and peritumoral arterial flow in the same lesion strongly suggests malignancy.

Quantification of the individual enantiomer plasma concentrations of the candidate antimalarial agent N4-[2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]-8-quinolinyl] - 1,4-pentanediamine (WR 238,605).

A high-performance liquid chromatographic method was developed to quantitate the plasma concentrations of the individual enantiomers of a candidate 8-aminoquinoline antimalarial agent WR 238,605 (I). The method employed one-step liquid extraction of a 0.5-ml plasma sample followed by direct injection of the extract through a chiral column and detection by fluorescence. Quantification was achieved using an internal standard. The limit of quantification was 10 ng/ml for each enantiomer. The method is sufficiently sensitive to quantitate the plasma concentrations of both enantiomers for 30 days following a single oral dose of 400 mg of the antimalarial agent administered as the racemic succinate salt to healthy human male volunteers. In nearly all samples taken 12 h to 30 days post-dose from three subjects, the difference in the plasma concentrations of the two enantiomers is less than 10%.

Aminosulfhydryl and aminodisulfide compounds enhance binding of the glucocorticoid receptor complex to deoxyribonucleic acid-coated cellulose and to chromatin.

In the presence of amine-containing sulfhydryl compounds, binding of heat-transformed cytosolic rat liver glucocorticoid receptor complex (GRC) to double-stranded calf thymus DNA-coated cellulose and to rat liver chromatin was enhanced up to 10-fold. These observations were made under conditions when a maximum of 8% of the total GRC bound to DNA in the absence of test compound. Compounds which did not contain both a sulfhydryl and amine group were inactive. Phosphorothioate derivatives of the active sulfhydryl compounds were also inactive. However, pretreatment of the phosphorothioate compounds with alkaline phosphatase restored activity. Upon centrifugation at 8800g, amine-containing disulfide compounds at millimolar concentrations caused considerable sedimentation of the GRC in the absence of DNA-coated cellulose or chromatin and no apparent increase in GRC binding to DNA or chromatin. Amine-containing disulfide compounds at micromolar concentrations did not cause heavy sedimentation of the GRC and enhanced binding of the GRC to DNA-coated cellulose up to 9.5-fold. Thus, diaminosulfhydryl compounds and the disulfide 1,18-diamino-6,13-diaza-9,10-dithiaoctadecane (WR 149,024) possess both the ability to restore and preserve the steroid binding capacity of the glucocorticoid receptor and to enhance binding of the GRC to DNA and chromatin.

Plasmodium falciparum: role of absolute stereochemistry in the antimalarial activity of synthetic amino alcohol antimalarial agents.

The (+)-isomers of mefloquine and its threo analog are 1.69 to 1.95 times more active than the (-)-isomers against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum in vitro. This large a differential between the activity of (+)- and (-)-isomers was not observed for other synthetic amino alcohol antimalarial agents containing a piperidine ring. The enantiomers of amino alcohol antimalarial agents in which the amine is part of an acyclic group, such as in halofantrine, displayed little, if any, differential antimalarial activity. Thus, the effect of absolute stereochemistry of the amino alcohol antimalarial agents on antimalarial activity appears to depend upon both the flexibility of the amine portion of the molecule and the structure of the aromatic portion of the molecule.

Structure-activity relationship of the preservation and restoration of glucocorticoid receptors in rat hepatocytes and rat liver homogenates by sulfhydryl, phosphorothioate and disulfide compounds.

The purpose of this work was to examine whether the ability of dithiothreitol to preserve the steroid-binding capacity of glucocorticoid receptors in subcellular preparations is specific or a general property of sulfhydryl compounds and selected phosphorothioate and disulfide derivatives. A further goal was to see if this effect could be demonstrated in intact cells. The ability to preserve the steroid-binding capacity of the glucocorticoid receptor is not a universal property of all sulfhydryl compounds since many of the compounds tested were inactive. The steroid-binding capacity of the glucocorticoid receptor of the 100,000 g supernatant of rat liver homogenate is preserved/restored by sulfhydryl compounds containing a mercaptoethylamine or mercaptopropylamine subunit. However, small changes in the structure of the sulfhydryl compound such as the rearrangement of a methylene group significantly alter its effectiveness. All of the phosphorothioates examined are derivatives of active sulfhydryl compounds and are effective in preserving steroid-binding. The extent of metabolism of the phosphorothioates and their failure to restore steroid-binding capacity after short-time exposure to receptor preparations are consistent with the sulfhydryl form being the active form of the phosphorothioates. S-2-(3-Amino-propylamino)ethylphosphorothioic acid (WR 2721) preserved steroid-binding capacity in isolated intact rat hepatocytes down to 25 microM demonstrating that concentrations obtainable in whole animals are effective with intact cells. Disulfide derivatives of active sulfhydryl compounds are either immediately toxic or ineffective except for 1,18-diamino-6,13-diaza-9,10-dithiaoctadecane (WR 149,024) which is more effective than its corresponding sulfhydryl. The demonstration that some sulfhydryl-forming compounds preserve the steroid-binding capacity of glucocorticoid receptors in intact cells at potentially physiologically obtainable concentrations suggests a potential role for these or similar compounds to bolster the efficacy of conventional glucocorticoid therapy.

Rapid and sensitive quantitative analysis of the new antimalarial N4-[2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]-8- quinolinyl]-1,4-pentanediamine in plasma by liquid chromatography and electrochemical detection.

A rapid, sensitive and simple method was developed for the quantitation of the plasma concentration of N4-[2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]-8- quinolinyl]-1,4-pentanediamine, a new antimalarial active against Plasmodium vivax. N4-(5-Hexoxy-6-methoxy-4-methyl-8-quinolinyl)-1,4- pentanediamine diphosphate, a similar 8-aminoquinoline, was used as an internal standard. The method involves sample clean-up by a prepacked cyano solid-phase column followed by reversed-phase liquid chromatography and oxidative electrochemical detection at +0.95 V. The assay has been validated to 5 ng/ml of plasma and is sensitive to 1 ng/ml of plasma. The results of a pilot study assessing the relative oral bioavailability of two different salt forms of the new antimalarial in dogs show the usefulness of the method for animal and human pharmacokinetic studies.