pyrimidinones and Acute-Disease

The incidence of acute B hepatitis is decreasing due to socioeconomical changes and the implementation of vaccination programs. Nevertheless it is potentially severe, causing approximately 30% of acute liver failures in Spain. Pharmacological treatment of acute B hepatitis has become a matter of issue over the last decade. This text offers a review of the published data and international guidelines. Most published studies have a low methodological quality and lamivudine was used as treatment in all of them. A survival improvement with prompt treatment has been shown in acute liver injury and probably in severe acute hepatitis (total bilirubin>10mg/dl and INR>1.5). International guidelines support treatment in these cases, but there is no consensus on the drug to use or the length of treatment.

Topics: Acute Disease; Adenine; Antiviral Agents; Guanine; Hepatitis B; Humans; Lamivudine; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Spain; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.

Topics: Acute Disease; Adenosine; Animals; Depression, Chemical; Erythrocytes; Glomerulonephritis; Humans; Inflammation; Leukopenia; Lipopolysaccharides; Mice; Neurotransmitter Uptake Inhibitors; Pancreatitis; Pyrimidinones; Quinazolines; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Animals; Bone Marrow; Bone Marrow Transplantation; Cyclophosphamide; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Leukemia; Lymphoma; Mechlorethamine; Neoplastic Stem Cells; Photosensitivity Disorders; Podophyllotoxin; Pyrimidinones; Rats; Transplantation, Autologous

The discovery that purine nucleoside phosphorylase (PNP) deficiency leads to T-cell lymphopenia was the basis for introducing PNP inhibitors for T-cell leukemias. Forodesine is an orally bioavailable PNP inhibitor with picomolar potency. Because T lymphoblasts and indolent chronic lymphocytic leukemia (CLL) B cells inherently elicit favorable pharmacokinetics to accumulate deoxyguanosine triphosphate (dGTP), forodesine demonstrated promising activity in preclinical and clinical settings for patients with T-cell acute lymphoblastic leukemia (T-ALL) and B-cell CLL (B-CLL). However, the use of forodesine in B-cell ALL (B-ALL) is unknown.. Leukemic blasts obtained from pediatric patients with de novo B-ALL (n = 10) were incubated with forodesine and deoxyguanosine (dGuo), and the biological end points of apoptosis, intracellular dGTP accumulation, and inhibition of RNA and DNA synthesis were measured. Additionally, adult patients with B-ALL (n = 2) were intravenously infused with 80 mg/m(2)/d daily for 5 days. After therapy, clinical response, toxicity, laboratory biomarkers including PNP enzyme inhibition, and plasma forodesine, dGuo, and intracellular dGTP levels were analyzed.. Our in vitro investigations demonstrated that forodesine treatment inhibited proliferation and induced modest apoptosis in de novo B-ALL lymphoblasts. There was time-dependent accumulation of dGTP and inhibition of RNA and DNA synthesis. During therapy, neither patient achieved a complete response (CR), but there was disease stabilization for several weeks in both patients. There was significant maintained inhibition of PNP enzyme in red blood cells, accumulation of forodesine and dGuo in plasma, and intracellular dGTP accumulation in both patients.. Our preclinical and clinical investigations suggest that forodesine has activity in B-ALL. However, it needs to be either infused with dGuo or combined with established chemotherapeutic agents based on mechanistic rationale.

Topics: Acute Disease; Adolescent; Adult; Apoptosis; Child; Child, Preschool; Deoxycytidine Kinase; Deoxyguanine Nucleotides; Female; Humans; Infant; Male; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Pyrimidinones; Young Adult

The uric acid metabolism pathway is more similar in primates and humans than in rodents. However, there are no reports of using primates to establish animal models of hyperuricaemia (HUA).. To establish an animal model highly related to HUA in humans.. Inosine (75, 100 and 200 mg/kg) was intraperitoneally administered to adult male rhesus monkeys (. Inosine (200 mg/kg) effectively increased the SUA level in rhesus monkeys from 51.77 ± 14.48 at 0 h to 178.32 ± 14.47 μmol/L within 30 min and to peak levels (201.41 ± 42.73 μmol/L) at 1 h. PNP mRNA level was increased, whereas XO mRNA and protein levels in the liver were decreased by the inosine group compared with those in the control group. No changes in mRNA and protein levels of the renal uric acid transporter were observed. Ulodesine, allopurinol and febuxostat eliminated the inosine-induced elevation in SUA in tested monkeys.. An acute HUA animal model with high reproducibility was induced; it can be applied to evaluate new anti-HUA drugs

Topics: Acute Disease; Allopurinol; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Febuxostat; Hyperuricemia; Imino Furanoses; Inosine; Macaca mulatta; Male; Pyrimidinones; Reproducibility of Results; Uric Acid

Topics: Acute Disease; Adult; Antineoplastic Agents; Granuloma; Heart Failure; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Myocarditis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Biomarkers have improved the clinical application of numerous targeted agents used to treat solid tumors. In melanoma, the finding that approximately 60% of tumor cells harbor specific Val600 mutations of BRAF has increased the likelihood of response to certain agents aimed at inhibiting the mutant kinase. While dabrafenib is an effective anti-tumor agent with acceptable tolerability in patients with BRAF-mutated melanoma, we report the development (and outcome) of a previously unpublished acute toxic reaction observed in a patient receiving the drug.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Female; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.. Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.. This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.

Topics: Acute Disease; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mediastinal Neoplasms; Membrane Proteins; Neoplasm Recurrence, Local; Neoplasms, Germ Cell and Embryonal; Point Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; Tumor Suppressor Protein p53; Young Adult

Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 microg/kg; sildenafil-analog (n=5) 500 microg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes . cm . sec(-5) at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.

Topics: Acute Disease; Animals; Blood Pressure; Cardiopulmonary Bypass; Hypertension, Pulmonary; Milrinone; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Reperfusion Injury; Sildenafil Citrate; Sulfones; Sus scrofa; Vascular Resistance

The immunological and clinical benefits of structured treatment interruptions (STIs) during primary HIV-1 infection remain largely unclear.. Eight patients identified during primary HIV-1 infection were immediately treated with HAART and underwent subsequent STIs after reaching complete viral suppression of HIV-RNA in peripheral plasma. HAART was re-initiated if either HIV-1 RNA >5000 copies/ml, CD4-cells <200 cells/microl or symptomatic HIV-1 disease was observed.. After treatment discontinuation, four of eight patients were able to persistently control HIV-1 viremia below 5000 copies/ml until the last time point of follow-up (median 3 years). CD4-cell counts were within the interquartile range of untreated individuals compared to historical reference data from the MACS cohort. In the remaining study subjects persistent virological control was not reached despite repeated STIs. Moreover, compared to the MACS cohort repetitive virological failures during STIs appeared to induce an accelerated decline of CD4-cells.. Spontaneous HIV-1 control after treated primary HIV-1 infection was possible in four out of eight individuals, however, if STIs after treated primary infection ameliorate the overall HIV-1 disease progression remains unknown. In the absence of viral control, repetitive viral exposure during STIs might be associated with accelerated decline of CD4-cell counts.

Topics: Acute Disease; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; Follow-Up Studies; Histocompatibility Testing; HIV Seropositivity; HIV-1; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Retrospective Studies; RNA, Viral; Stavudine; Treatment Outcome; Zidovudine

Topics: Acute Disease; Adult; Anti-HIV Agents; Drug Eruptions; Exanthema; HIV Infections; Humans; Lopinavir; Male; Occupational Exposure; Pyrimidinones; Ritonavir; Skin Diseases, Vesiculobullous

To examine the effects of treatment with valproate on brain 5-HT2A receptors in acute manic patients using positron emission tomography (PET) and [18F]-setoperone.. Patients with DSM-IV bipolar I disorder-manic episode were recruited. Patients were drug free or drug naïve at the time of baseline PET scan. All patients were treated with valproate and one patient received lithium in addition to valproate for 3-5 weeks following which they had a post-treatment PET scan. The effect of treatment on brain 5-HT2A receptor binding was determined using statistical parametric mapping (SPM) and region of interest (ROI) analyses. Of the 12 manic patients recruited, seven patients had both baseline and post-treatment PET scans.. All seven patients improved with treatment and were in remission at the time of the second PET scan. Both SPM and ROI analyses showed that treatment with mood stabilizers had no significant effect on brain 5-HT2A receptor binding in manic patients.. This study suggests that changes in brain 5-HT2A receptors are not involved in the antimanic effects of mood stabilizers however, we cannot exclude the possibility of 5-HT2A receptor involvement in down-stream signaling pathways.

Topics: Acute Disease; Adult; Antimanic Agents; Bipolar Disorder; Brain; Contrast Media; Female; Humans; Lithium; Male; Middle Aged; Positron-Emission Tomography; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Valproic Acid

Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension.. Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound.. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05).. The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

Topics: Acute Disease; Animals; Disease Models, Animal; Hypertension, Pulmonary; Piperazines; Purines; Pyrimidinones; Random Allocation; Sildenafil Citrate; Sulfones; Swine; Vasodilator Agents

The pharmacological profile of the new CCK1 receptor antagonist IQM-97,423, (4aS,5R)-2-benzyl-5-(tert-butylaminocarbonyl-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine, was examined in in vitro and in vivo studies and compared with typical CCK1 antagonists such as devazepide and lorglumide. IQM-97,423 showed a high affinity at [3H]-pCCK8-labeled rat pancreatic CCK1 receptors, and was virtually devoid of affinity at brain CCK2 receptors. IQM-97,423 antagonized CCK8S-stimulated alpha-amylase release from rat pancreatic acini with a potency similar to devazepide and much higher than lorglumide. In the guinea pig isolated longitudinal muscle-myenteric plexus preparation, IQM-97,423 produced a full antagonism of the contractile response elicited by CCK8S and a weaker effect on the contraction elicited by CCK4, suggesting a selective antagonism at CCK1 receptors. The protective effect of IQM-97,423 and devazepide was tested in two models of acute pancreatitis in rats, induced by injection of cerulein or by combined bile and pancreatic duct obstruction. The new compound fully prevented the cerulein-induced increase in plasma pancreatic enzymes and in pancreas weight with a potency similar to devazepide. In common bile-pancreatic duct ligature-induced acute pancreatitis, IQM-97,423 partially prevented, like devazepide, the increase in plasma pancreatic enzyme activity and in pancreas weight. Consequently, the pyridopyrimidine derivative IQM-97,423 is a potent and highly selective CCK1 receptor antagonist with preventive effects in two experimental models of acute pancreatitis and a potential therapeutic interest.

Topics: Acute Disease; alpha-Amylases; Animals; Binding, Competitive; Cerebral Cortex; Cholecystokinin; Devazepide; Disease Models, Animal; Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Neuromuscular Junction; Pancreatitis; Peptide Fragments; Proglumide; Pyrimidinones; Rats; Rats, Wistar; Receptor, Cholecystokinin A

Perioperative pulmonary hypertension remains a clinical challenge. The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available. This study evaluated the effects of a new intravenous sildenafil analogue--UK 343-664--compared with milrinone during acute pulmonary hypertension in a porcine model of thromboxane-induced pulmonary hypertension.. After acute pulmonary hypertension, 24 adult swine were randomized to 3 groups. Group 1 (n = 9) received an intravenous dose of 500 microg of UK 343-664, group 2 (n = 8) received milrinone 50 mg/kg, and group 3 (n = 7) received 10 mL of normal saline solution. All agents were administered for more than 5 minutes. Data were recorded continuously for 30 minutes.. Both milrinone and UK 343-664 partially reversed thromboxane-induced pulmonary hypertension, with a notable decrease in mean pulmonary artery pressure and pulmonary vascular resistance and a concomitant increase in cardiac output. In addition, milrinone improved right ventricular contractility but produced marked systemic vasodilatation. In contrast, the administration of UK 343-664 was associated with pulmonary vasodilatation, without appreciable changes in systemic arterial pressure or vascular resistance.. Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity. Potential uses for this new phosphodiesterase enzyme type V inhibitor warrant further study.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Animals; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Hemodynamics; Hypertension, Pulmonary; Milrinone; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pyrimidinones; Random Allocation; Sus scrofa; Vasodilator Agents

Adenosine protects against cellular damage and dysfunction under several adverse conditions including inflammation and ischemia. In this study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on experimental acute pancreatitis induced by choline-deficient and ethionine-supplemented diet in mice. KF24345, administered with the diet onset and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and serum tumor necrosis factor-alpha elevation and ultimately decreased mortality. Therapeutic treatment with KF24345, which started 32 h after the diet onset, also decreased mortality. The beneficial effect of KF24345 on mortality was abolished by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A(2A) receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet onset increased plasma adenosine concentrations in mice with acute pancreatitis. These results suggest that KF24345 shows anti-pancreatitis effects via endogenous adenosine and adenosine A(2A) receptors. The adenosine uptake inhibition could be a new therapeutic approach for acute pancreatitis.

Topics: Acute Disease; Adenosine; Amylases; Animals; Choline Deficiency; Diet; Female; L-Lactate Dehydrogenase; Mice; Neurotransmitter Uptake Inhibitors; Organ Size; Pancreas; Pancreatitis; Pyrimidinones; Quinazolines; Time Factors; Tumor Necrosis Factor-alpha

Adenosine shows protective effects against cellular damage and dysfunction under several adverse conditions such as inflammation and ischemia. In the current study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1,3 )-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on cerulein-induced acute pancreatitis in mice to investigate whether inhibition of adenosine uptake could ameliorate the severity of acute pancreatitis.. Acute pancreatitis was induced in mice with six intraperitoneal injections of cerulein (50 microg/kg each) at hourly intervals.. The cerulein injection increased activities of serum amylase and lipase and caused pathologic changes such as interstitial edema, polymorphonuclear cell infiltration, and acinar cell necrosis in the pancreas. KF24345 (10 mg/kg p.o.) ameliorated all these changes observed in mice with acute pancreatitis, and the suppressing effect of KF24345 on the elevation in serum amylase activity was abolished by the treatment with 8-(p-sulfophenyl)theophylline, an adenosine receptor antagonist. In addition, 2-(aminocarbonyl)- -(4-amino-2,6-dichlorophenyl)-4-[5,5-bis-(4-fluorophenyl)pentyl]-1-piperazineacetamide (R75231) and dipyridamole, other adenosine uptake inhibitors, also decreased the elevated serum amylase activity.. These are the first demonstrations that the adenosine uptake inhibitors ameliorate cerulein-induced acute pancreatitis in mice, and these data suggest that adenosine uptake inhibition could ameliorate the severity of acute pancreatitis in vivo.

Topics: Acute Disease; Adenosine; Amylases; Animals; Biological Transport; Ceruletide; Dipyridamole; Female; Lipase; Mice; Mice, Inbred BALB C; Models, Chemical; Pancreatitis; Piperazines; Pyrimidinones; Quinazolines; Theophylline

Analogues of the previously reported potent and highly selective CCK(1) receptor antagonist (4aS, 5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1, 2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK(1) receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3, 3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK(1) receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.

Topics: Acute Disease; Administration, Oral; Animals; Cerebral Cortex; Ceruletide; Hyperkinesis; In Vitro Techniques; Injections, Intraperitoneal; Male; Mice; Pancreas; Pancreatitis; Pyridines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship; Tryptophan

The biochemical events that take place during acute hemolysis of G6PD-deficient subjects in favism are far from being elucidated. Evidence is here reported for a constantly and heavily disordered calcium homeostasis in the erythrocytes from seven favic patients. The abnormality, ie, a significantly impaired calcium ATPase activity and a parallel marked increase of intracellular calcium levels, was characteristic of the acute hemolytic crisis although unrelated to the attendant reticulocytosis. Concomitantly, a remarkable decrease of intracellular potassium was also observed. The mean +/- SD Ca2+-ATPase activity in the favic patients was 20.8 +/- 7.8 mumol Pi/g Hb/h compared with 37.2 +/- 8.5 in the matched controls represented by 12 healthy G6PD-deficient subjects (P less than .001). The mean +/- SD intraerythrocytic calcium content was 288 +/- 158 mumol/L of erythrocytes in the favic patients as compared with 22.0 +/- 8.2 in the G6PD-deficient controls (P less than .001). The intraerythrocytic potassium content was 76.6 +/- 19.3 mmol/L of erythrocytes in the favic patients and 106.6 +/- 8.2 in the G6PD-deficient controls (P less than .001). In vitro incubation of normal and G6PD-deficient erythrocytes with divicine, a pyrimidine aglycone present in fava beans and strongly implicated in the pathogenesis of favism, reproduces most of these events, including drop of calcium ATPase, increased intracellular calcium, and leakage of erythrocyte potassium.

Topics: Acute Disease; Calcium; Calcium-Transporting ATPases; Cell Separation; Erythrocyte Count; Erythrocytes; Favism; Homeostasis; Humans; In Vitro Techniques; Ion Channels; Male; Methemoglobin; Potassium; Pyrimidinones

Topics: Acute Disease; Adolescent; Adult; Aged; Analgesics; Chronic Disease; Drug Evaluation; Humans; Joint Diseases; Middle Aged; Pyrimidinones

Toxicological analysis of a Hungarian analgetics - Probon - of new chemical structure was carried out in experiment. A new technique was developed for quantitative analysis of the drug and its main metabolits in biological material. Distribution of Probon in various organs, grade of the metabolization in acute intoxication was also studied.

Topics: Acute Disease; Animals; Humans; Pyrimidinones; Rats