pyrimidinones and Body-Weight

Liver disease may alter the pharmacokinetics of antiretrovirals and produce changes in plasma protein binding. The aim was to evaluate the pharmacokinetics of total and unbound lopinavir (LPV) in HIV-infected patients with and without hepatitis C virus (HCV) coinfection. Fifty-six HIV+ patients receiving lopinavir/ritonavir (LPV/r) (group I = 24 controls; II = 23 HIV/HCV-coinfected; III = 9 cirrhotic HIV/HCV-coinfected) were included. Total (n = 56) and unbound (n = 36) LPV pharmacokinetic parameters were determined at steady-state using validated high-performance liquid chromatography with ultraviolet detection and high-performance liquid chromatography-tandem mass spectrometry methods, respectively. Pharmacokinetic parameters (plasma concentration just before drug administration, peak concentrations in plasma, times to maximum plasma concentration, areas under the plasma concentration-time curve from 0 to 12 hours, and CL/F/kg) of both total and unbound LPV were calculated by standard noncompartmental methods and differences among groups evaluated (Kruskal-Wallis test).LPV apparent oral clearance normalized to body weight (median, interquartile range) was 55 (40-68), 59 (44-69), and 71 (53-78) mL/h/kg for groups I, II, and III, respectively (II vs. I, P = 0.52; III vs. I, P = 0.16). The areas under the plasma concentration-time curve from 0 to 12 hours were 110.4 (80.9-135.2), 103.4 (85.5-131.3), and 92.8 (87.4-116.3) microg h/mL for groups I, II, and III, respectively (II vs. I, P = 0.68; III vs. I, P = 0.71). Chronic liver impairment produced a slight, although not significant, decrease in plasma protein binding. The free-fraction of LPV increased ( approximately 21%) from 0.97% (0.80-1.06) in HIV+/HCV- patients to 1.18% (0.89-1.65) in HIV/HCV+ cirrhotic patients. The apparent oral clearance of unbound LPV (CLu/F/kg) in cirrhotic patients did not change significantly, supporting the concept that the clearance of unbound LPV in liver disease is not affected after being inhibited by low-dose ritonavir co-administration.LPV total and unbound pharmacokinetics were not affected by hepatic impairment, suggesting that no adjustment of LPV/r dose is required for HIV/HCV-coinfected patients with and without cirrhosis and moderate impairment of liver function.

Topics: Adult; Area Under Curve; Body Weight; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Liver Function Tests; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir; Spectrophotometry, Ultraviolet; Ultrafiltration; Ultrasonography

To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in body fat composition.. A prospective, non-randomized study.. HIV clinic of a University Hospital.. HIV-infected subjects who had virological failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment and 16 completed the full 48-week study period.. Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. LPV trough plasma concentrations were measured at baseline and weeks 4, 8, 12, 24, 36 and 48. Body fat composition was quantified by computerized tomographic scanning at baseline, and weeks 24 and 48.. LPV trough concentrations correlated with absolute and proportional changes in limb fat from baseline to week 48. Significant differences were found in mean LPV trough concentrations between patients losing less than 5% of limb fat, those experiencing a limb fat loss between 5 and 20%, and those losing more than 20% at week 24 [mean (SD), 4.67 (1.67); 8.57 (1.77); 9.49 (2.67) microg/ml, respectively; P=0.013] and week 48 [mean (SD), 4.5 (2.24); 7.04 (1.77); 9.7 (2.8) microg/ml, respectively; P=0.027]. Most patients losing more than 5% of limb fat during LPV/r therapy had mean LPV trough concentrations > or = 8 microg/ml.. In patients receiving salvage therapy with LPV/r there was an association between LPV plasma trough concentrations and limb fat loss. The risk of peripheral limb fat loss may be greater among patients achieving higher LPV trough concentrations.

Topics: Adipose Tissue; Anti-HIV Agents; Area Under Curve; Body Composition; Body Mass Index; Body Weight; CD4 Lymphocyte Count; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir; Salvage Therapy; Tomography, X-Ray Computed

Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Topics: Adult; Area Under Curve; Body Weight; Capsules; Drug Therapy, Combination; Excipients; Female; Gelatin; Hepatitis, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Saquinavir; Sex Characteristics; Treatment Failure; Viral Load

Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Cold Temperature; Diabetes Mellitus, Type 2; Diet; Dimethylphenylpiperazinium Iodide; Energy Metabolism; Fatty Liver; Glucose Intolerance; Insulin Resistance; Male; Melanocortins; Mice, Inbred C57BL; Mice, Obese; Obesity; Pyrimidinones; Receptor, Melanocortin, Type 4; Receptors, Nicotinic; Thermogenesis; TRPM Cation Channels

Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients.

Topics: 8,11,14-Eicosatrienoic Acid; Adiponectin; Adipose Tissue; Animals; Arachidonic Acid; Body Weight; Delta-5 Fatty Acid Desaturase; Diet, High-Fat; Energy Metabolism; Enzyme Inhibitors; Fatty Acid Desaturases; Gene Expression; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Male; Mice, Inbred C57BL; Obesity; Pyrimidinones; Pyrrolidinones; Reverse Transcriptase Polymerase Chain Reaction; Weight Loss

Merocyanine 540-mediated photodynamic therapy (MC540-PDT) has been used in clinical trials for the purging of autologous hematopoietic stem cell grafts. When the same combinations of dye and light were applied to human peripheral blood lymphocytes, a broad range of T- and B-cell functions were impaired, prompting speculations about a potential role of MC540-PDT in the prophylaxis of graft-versus-host disease (GVHD). We here report on the effects of MC540-PDT on in vitro functions of murine lymphocytes as well as a preliminary evaluation of MC540-PDT for the prevention of GVHD in murine models of allogeneic bone marrow transplantation. Mixed lymphocyte reactions, proliferative responses to lectins, interleukin-2 and lipopolysaccharide, T-cell-mediated lysis, and NK activity were all inhibited by moderate doses of MC540-PDT. Whether MC540-PDT reduced the incidence and/or the severity of GVHD in murine models of allogeneic hematopoietic stem cell transplantation depended on the composition of the mismatched grafts and the intensity of the preparative regimen. MC540-PDT was only beneficial (i.e. reduced the incidence and/or severity of GVHD) when the spleen cell content of grafts was low and/or the radiation dose of the preparative regimen was not myeloablative, and, therefore, may have encouraged mixed chimerism.

Topics: Animals; B-Lymphocytes; Body Weight; Bone Marrow Cells; Bone Marrow Transplantation; Cell Proliferation; Cell Survival; Female; Graft vs Host Disease; Killer Cells, Natural; Light; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; T-Lymphocytes; Transplantation, Homologous

Calcitonin gene-related peptide-α (CGRPα) is a classic marker of peptidergic nociceptive neurons and is expressed in myelinated and unmyelinated dorsal root ganglia (DRG) neurons. Recently, we found that ablation of Cgrpα-expressing sensory neurons reduced noxious heat sensitivity and enhanced sensitivity to cold stimuli in mice. These studies suggested that the enhanced cold responses were due to disinhibition of spinal neurons that receive inputs from cold-sensing/TRPM8 primary afferents; although a direct role for TRPM8 was not examined at the time.. Here, we ablated Cgrpα-expressing sensory neurons in mice lacking functional TRPM8 and evaluated sensory responses to noxious heat, cold temperatures, and cold mimetics (acetone evaporative cooling and icilin). We also evaluated thermoregulation in these mice following an evaporative cold challenge. We found that ablation of Cgrpα-expressing sensory neurons in a Trpm8-/- background reduced sensitivity to noxious heat but did not enhance sensitivity to cold stimuli. Thermoregulation following the evaporative cold challenge was not affected by deletion of Trpm8 in control or Cgrpα-expressing sensory neuron-ablated mice.. Our data indicate that the enhanced behavioral responses to cold stimuli in CGRPα sensory neuron-ablated mice are dependent on functional TRPM8, whereas the other sensory and thermoregulatory phenotypes caused by CGRPα sensory neuron ablation are independent of TRPM8.

Topics: Animals; Body Temperature Regulation; Body Weight; Calcitonin Gene-Related Peptide; Cell Count; Cold Temperature; Diphtheria Toxin; Ganglia, Spinal; Heparin-binding EGF-like Growth Factor; Hot Temperature; Humans; Hyperalgesia; Male; Mice; Mice, Transgenic; Neurofilament Proteins; Phosphopyruvate Hydratase; Pyrimidinones; Sensory Receptor Cells; Sensory Thresholds; TRPM Cation Channels

Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

Topics: Animals; Antineoplastic Agents; Aprepitant; Biological Transport; Body Weight; Cisplatin; Dexamethasone; Eating; Kaolin; Male; Morpholines; Ondansetron; Pyridines; Pyrimidinones; Rats; Substance P

The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.. Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.. Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).. This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Body Weight; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Plasma; Pyridines; Pyrimidinones; Rifabutin; United Kingdom

Reduced lopinavir concentrations have been demonstrated with use of the capsule formulation during the third trimester of pregnancy. This study determined lopinavir exposure with an increased dose of the new tablet formulation during the third trimester.. International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is a prospective nonblinded pharmacokinetic study in HIV-infected pregnant women, including a cohort receiving 2 lopinavir/ritonavir tablets (400 mg/100 mg) twice daily during the second trimester, 3 tablets (600 mg/150 mg) twice daily during the third trimester, and 2 tablets (400 mg/100 mg) twice daily post delivery through 2 weeks postpartum.. Steady-state 12-hour pharmacokinetic profiles were performed during pregnancy and at 2 weeks postpartum. Lopinavir and ritonavir were measured by reverse-phase high-performance liquid chromatography (detection limit, 0.09 mcg/mL).. Thirty-three women were studied. Median lopinavir AUC for the second trimester (n = 11), third trimester (n = 33), and postpartum (n = 27) were 72, 96, and 133 mcg x hr/mL, respectively. Median minimum lopinavir concentrations were 3.4, 4.9, and 6.9 mcg/mL.. The higher lopinavir/ritonavir tablet dose (600 mg/150 mg) provided exposure during the third trimester similar to the average AUC (98 mcg x hr x mL(-1) in nonpregnant adults taking 400 mg/100 mg twice daily. The higher dose should be used during the second and third trimesters of pregnancy. Postpartum dosing can be reduced to standard dosing before 2 weeks postpartum.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Body Weight; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethnicity; Female; Gestational Age; HIV Infections; Humans; Lopinavir; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Pyrimidinones; Racial Groups; Zidovudine

The impact of prolonged direct antiviral therapy on hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B is poorly understood. We quantitatively assessed serum HBsAg levels during 3 years of telbivudine treatment, as well as their relationship with virologic and biochemical characteristics in 162 hepatitis B e antigen-positive patients who maintained undetectable serum hepatitis B virus (HBV) DNA long-term. Telbivudine treatment progressively reduced serum HBsAg levels (mean ± SD) from baseline (3.8 ± 0.6 log₁₀ IU/mL) to treatment week 24 (3.4 ± 0.7 log₁₀ IU/mL), treatment year 1 (3.3 ± 0.8 log₁₀ IU/mL), and treatment year 3 (3.0 ± 1.4 log₁₀ IU/mL) (P <0.0001). In this patient population, HBsAg loss was observed in nine (6%) of 162 patients through year 3. During the first year of treatment, three patterns of HBsAg decline were observed: rapid (≥ 1 log₁₀ IU/mL) in 32 patients, slow (0-1 log₁₀ IU/mL) in 74 patients, and steady levels in 56 patients. These findings were associated with different likelihoods of HBsAg loss during long-term telbivudine therapy. Eight of 32 patients with rapid HBsAg decline versus none of 56 patients with steady HBsAg levels achieved HBsAg loss at year 3 (P = 0.0024). HBV genotype was a significant determinant for HBsAg kinetics, with the fastest decline in genotype A patients. In patients with subsequent HBsAg loss, viral antigens were already undetectable in liver biopsy samples after 1 year of treatment. This was associated with markedly enhanced antiviral T cell reactivity.. In patients who have effective suppression of viral replication during telbivudine treatment, a rapid decline in serum HBsAg levels during the first year may identify those with a greater likelihood of achieving HBsAg clearance.

Topics: Adult; Antiviral Agents; Body Weight; Enzyme-Linked Immunosorbent Assay; Genotype; Hepatitis B Core Antigens; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Kinetics; Liver; Lymphocyte Activation; Nucleosides; Patient Selection; Pyrimidinones; Racial Groups; T-Lymphocytes; Telbivudine; Thymidine; Time Factors

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one], was evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 14-day study of diet-induced obese rats. GW803430 was evaluated subsequently for antidepressant-like effects in mice and rats. Acute and subchronic administration reduced immobility time in the mouse forced-swim test at doses of 3 (acute) and 3 and 10 (chronic) mg/kg p.o., an effect that was absent in MCHR1(-/-) mice. Combined subeffective doses of GW803430 (0.3 and 1 mg/kg p.o.) and imipramine (5 mg/kg) produced a robust antidepressant-like response. The compound was also active in the tail suspension test at a dose of 10 mg/kg p.o. GW803430 (30 mg/kg p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of submissive behavior that may predict antidepressant onset. GW803430 decreased marble burying in mice at doses of 3, 10, and 30 mg/kg p.o., an assay that detects anxiolytic-like effects. Thus, GW803430 produces robust antiobesity and antidepressant-like effects in rats and mice at doses that compete for central MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for future drug discovery efforts.

Topics: Animals; Anti-Obesity Agents; Antidepressive Agents; Autoradiography; Behavior, Animal; Body Weight; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Mice; Mice, Knockout; Motor Activity; Obesity; Protein Binding; Pyrimidinones; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptors, Somatostatin; Social Dominance; Swimming; Thiophenes

Lopinavir is a potent protease inhibitor (PI) used for the treatment of HIV infection. Different lopinavir target trough concentrations (C(troughs)) were previously determined according to patient treatment histories: 1 mg/l for PI-naive patients, and 4 and 5.7 mg/l for PI-experienced patients. However, the probability to achieve these target C(troughs) with the current 400 mg twice-daily or 800 mg once-daily doses of the new tablet form, and the influence of body weight on this probability are unknown.. A population pharmacokinetic model for lopinavir was developed using data from 424 HIV type-1-infected patients, and the final model was used to estimate the probability to achieve target C(troughs) via Monte Carlo simulations.. A one-compartment model adequately described the data. Mean population estimates (percentage interindividual variability) were 4.61 l/h (36%) for apparent clearance (CL/F) and 63.2 l (70%) for apparent distribution volume. Body weight was found to explain the interindividual variability of lopinavir CL/F. Probability to achieve the 1 mg/l target C(trough) was >96% for the twice-daily dose and comprised between 80% and 90% for the once-daily dose. The probability to achieve the 4 and 5.7 mg/l target C(troughs) with the twice-daily dose significantly decreased when body weight increased (from 76% to 61% and from 56% to 37% respectively, for body weights increasing from 50 to 90 kg).. These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients.

Topics: Adolescent; Adult; Aged; Body Weight; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Models, Statistical; Population Surveillance; Pyrimidinones; Tablets

Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.

Topics: Animals; Body Weight; Mice; Mice, Inbred AKR; Models, Molecular; Molecular Structure; Pyrimidinones; Receptors, Pituitary Hormone; Structure-Activity Relationship; Sulfhydryl Compounds

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

Topics: Adolescent; Age Factors; Algorithms; Anti-HIV Agents; Area Under Curve; Body Weight; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Infant; Infant, Newborn; Lopinavir; Male; Models, Statistical; Population; Pyrimidinones; Reproducibility of Results; Retrospective Studies; Sex Factors; Spectrophotometry, Ultraviolet

Lopinavir is one of the most-widely used protease inhibitors in the treatment of HIV-1 infected patients. Concentration-effect relationships have been described for both antiviral activity and toxicity. Less is known about patient characteristics that may determine interpatient variability in lopinavir plasma concentrations. A database was created containing all Therapeutic Drug Monitoring (TDM) results collected at our Department. Patients were included if they were using lopinavir twice daily for at least two weeks; subjects who were known to be nonadherent (based on either a lopinavir concentration <0.2 mg/L or suspected by the physician) were excluded. Demographic data were collected from TDM application forms and patient charts. Patients attending one of the 22 HIV treatment centers in The Netherlands. The Department of Clinical Pharmacy is a national referral center for TDM of antiretroviral agents. Lopinavir concentration ratios (CRs) were calculated for each patient by dividing the individual plasma concentration by the time-adjusted population value. Relationships with lopinavir CRs were tested using regression analysis and analysis of variance. A total of 802 patients were included (607 males; 150 females; 45 unknown). The age and body weight of the patients ranged from 18 to 74 years (mean 42) and 42 to 121 kg (mean 72), respectively. Race was known for 756 persons: Caucasian 76%, African 18% and Asian 6%. The median (+ interquartile range, IQR) lopinavir CR was 0.98 (IQR: 0.67-1.31). Body weight showed an inverse relationship with lopinavir CR (F = 23.1; P < 0.001). Age was not related with lopinavir CR (P = 0.99). Female patients had a significantly higher lopinavir CR than males: 1.18 vs. 1.03 (P = 0.005); race was not associated with differences in lopinavir CR. In a multivariate regression analysis body weight, but not gender, remained significantly related to lopinavir CR. Body weight is the only demographic factor that could be related to lopinavir exposure; clinicians should be alert for an increased risk of suboptimal antiviral efficacy in patients with high body weight, and for an increased risk of toxicity in patients with a low body weight.

Topics: Adolescent; Adult; Aged; Body Weight; Databases, Factual; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Regression Analysis; Retrospective Studies; Tissue Distribution

Mature male rats (SD strain, 8-week-old) were fed with a normal diet or a high cholesterol diet (HC: 1.5% cholesterol and 0.5% Na cholate in the normal diet) up to 8 weeks, and we examined how the vascular function level of the isolated thoracic aorta and the histological figures of some tissues including the aorta would change. 1) The contracting reactivity to phenylephrine (Phe, 10 microM) and the relaxing reactivity to acetylcholine (1 microM) measured thereafter remained unchanged during the period of aging and were not influenced by HC-feeding. The addition of L-arginine (Arg, 100 microM) did not affect the results. 2) The ability of the aorta to release NO and to relax, which was evaluated as the extent of the endothelium-dependent potentiation by NG-monomethyl-L-arginine (NMA) of the Phe contraction, did not change by HC-feeding up to 4 weeks, but appears to be attenuated after 8-week feeding. 3) The EC50 of NMA for the potentiation estimated without the addition of Arg remained unchanged, while the one in the presence of Arg gradually increased with aging but not with HC-feeding. 4) The histopathological study of the aorta and other tissues failed to detect any notable atherogenic changes in any of the HC-fed groups. The results indicate that under the experimental conditions employed, HC-feeding would not develop any significant atherogenic histopathological changes in the endothelium-smooth muscle preparation, but may induce some dysfunction in the NO-release mediated and auto-regulatory function of the vascular tone.

Topics: Acetylcholine; Aging; Animals; Aorta, Thoracic; Arginine; Body Weight; Cholesterol, Dietary; Endothelium, Vascular; Hypercholesterolemia; In Vitro Techniques; Male; Muscle, Smooth, Vascular; omega-N-Methylarginine; Phenylephrine; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Vasoconstriction

A study was carried out to evaluate the effect of cysteamine-HCl administration on gizzard ulceration and growth performance in broiler chicks. The effectiveness of the histamine H2-receptor antagonist, SKF 93479, in preventing gizzard ulcerations when given in combination with cysteamine-HCl was also examined. In the initial experiment cysteamine-HCl at the level of 2400 mg/kg of the diet caused severe gizzard ulceration and mortality and decreased feed intake and growth in chicks. The effect was not seen when cysteamine-HCl was administered at 600 or 1200 mg/kg of the diet. In Experiment 2 broiler chicks administered cysteamine-HCl at 1800 mg/kg of the diet had an increased incidence of gizzard ulceration and decreased growth performance. The severity of gizzard lesions and the depression of growth performance were not as great as in the group in Experiment 1 which received the 2400 mg/kg level of cysteamine-HCl. Addition of the H2 antagonist SKF 93479 at 54 mg/kg of the diet had no effect on improving gizzard ulcer score or growth performance in chicks which received cysteamine-HCl at the 1800 mg/kg of the diet level. From these data it appears that the administration of ulcerogenic levels of cysteamine-HCl in the chicken may involve a more complex pathogenesis in which factors other than acid hypersecretion are involved.

Topics: Animals; Body Weight; Chickens; Cysteamine; Drug Combinations; Gizzard, Avian; Histamine H2 Antagonists; Male; Poultry Diseases; Pyrimidinones; Stomach Ulcer

1,6-Dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazol (rimazolium, MZ-144) proved to be effective in all the analgesic assays used (independently of the nociceptive stimulus applied) (hot plate, tail flick, writhing tests, Randall-Selitto test, tail clip, surgical pain) differing in this respect from the nonsteroidal antiinflammatory analgetics. The analgesic, antiinflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared. The prostaglandin (PG) mediated pain (acetylcholine-, adenosine triphosphate- and acetic acid-induced writhing) was inhibited by all the three types of compounds, however, pain reaction where PGs are not involved (MgSO4-writhing) was inhibited only by rimazolium and morphine but not, or only slightly, by PG synthesis inhibitors. While the analgesic effect of rimazolium alone was not reversed by naloxone, the full analgesia evoked by the ineffective doses of morphine and rimazolium combinations was completely naloxone reversible (pA2 = 8.6). In addition, rimazolium produced weak analgesia by intrathecal administration, and its concomitant s.c. administration enhanced the analgesic effect of intrathecally administered morphine. Furthermore, chronic treatment with rimazolium failed to influence its analgesic activity, and no tolerance developed and no naloxone precipitated withdrawal syndrome could be seen. In addition, rimazolium did not substitute for morphine in morphine dependent rats, after morphine withdrawal, thus indicating that rimazolium lacks the capacity of producing opiate-like physiological dependence. Also rimazolium fails to show any indication of narcotic-like abuse liability by any of clinical assessments. Rimazolium, morphine and indometacin inhibited the carrageenin-induced edema formation. Gastrointestinal lesions produced by indometacin were depressed by rimazolium and enhanced by morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cats; Dogs; Drug Tolerance; Guinea Pigs; Indomethacin; Macaca mulatta; Male; Mice; Pyrimidinones; Rabbits; Rats; Reaction Time; Stomach Ulcer; Substance Withdrawal Syndrome; Substance-Related Disorders