The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), in man

The influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of meloxicam has been studied in 12 healthy male volunteers. Each subject received on two occasions a single IV injection of meloxicam 30 mg. The cholestyramine group received the material suspended in water 3 times a day. Compared to controls, cholestyramine accelerated the elimination of meloxicam. The mean terminal phase elimination half-life was reduced from 19.5 h to 12.7 h due to an increase in clearance of the drug (0.426 vs 0.636 l.h-1). Also, as a consequence of increased clearance in the presence of cholestyramine, the mean residence time of the drug in the body was significantly decreased (39%) P < 0.01. However, the volume of distribution for meloxicam was largely unaffected by cholestyramine which suggests that meloxicam undergoes gut recirculation. These changes are of the same magnitude as those previously reported for the structurally related piroxicam and are much smaller than those observed for tenoxicam.     

The CYP3A4 inhibitor intraconazole does not affect the pharmacokinetics of a new calcium-sensitizing drug levosimendan

Itraconazole is a potent inhibitor of CYP3A4 isoenzyme and it can cause clinically significant interactions with some other drugs. Levosimendan is a new calcium-sensitizing drug intended for congestive heart failure. We aimed to study possible interactions of itraconazole with levosimendan in healthy volunteers. Twelve healthy male volunteers were included into a randomized, double-blind, two-phase crossover study. A wash-out period of 4 weeks was held between the phases. The subjects were given orally itraconazole 200 mg or placebo daily for 5 days. On the fifth day, they received a single oral dose of 2 mg of levosimendan. Levosimendan plasma concentrations were determined up to 12 hours and ECG, heart rate, and blood pressure followed-up to 8 hours after intake of levosimendan. Itraconazole had no significant effects on the pharmacokinetic parameters of levosimendan. Neither were there any differences in heart rate, PQ-, QTc- or QRS intervals between the placebo and itraconazole phases. The systolic blood pressure was decreased slightly more (p < 0.05) during the itraconazole phase than during the placebo phase. In conclusion, because the potent CYP3A4 inhibitor itraconazole had no significant pharmacokinetic interaction with levosimendan, interactions with CYP3A4 inhibitor, and oral levosimendan are unlikely.     

The application of population pharmacokinetics to the drug development process

Population pharmacokinetics is playing an increasing role in clinical drug development. An overview of the population approach, including software and the advantages and limitations of the approach compared to the traditional approach to pharmacokinetic studies, is given. This paper also documents how the area has evolved over the past 15 years and addresses some of the issues that have arisen over the design and conduct of population studies. Finally, some alternative applications of the population approach are given for areas other than clinical drug development.     

Four new drugs for glaucoma: apraclonidine, brimonidine, dorzolamide and latanoprost

Glaucoma is in most of cases initially treated with drugs, viz. beta-blocking agents, miotics, sympathicomimetics and carbonic anhydrase inhibitors. The therapy of first choice is a beta-blocking agent, but in approximately 50% of the patients treated the effect becomes inadequate with time and combination therapy is necessary. Recently, four new antiglaucomatous agents have become available: apraclonidine, brimonidine, dorzolamide and latanoprost. Apraclonidine, an alpha 2-adrenergic agonist, is indicated for brief episodes of postlaser rise of the intraocular pressure. Longer treatment may lead to tolerance. Brimonidine, another alpha 2-adrenergic agonist, is indicated for long-term treatment of glaucoma; tolerance does not often occur. Dorzolamide is a local carbonic anhydrase inhibitor which lacks the systemic side effects seen after oral administration of carbonic anhydrase inhibitors. Latanoprost, a prostaglandin F2 alpha-derivative induces an effective decrease of the intraocular pressure if administered as monotherapy and has a good efficacy when combined with other drugs lowering the intraocular pressure. The new antiglaucomatous agents are a welcome addition to the pharmacotherapy, since in many cases they make it possible to postpone or avoid surgery.     

Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations

Oxidized low density lipoprotein (LDL) and acetyl LDL are recognized by the scavenger receptor class A type I/II (SR-AI/II) on macrophages and liver endothelial cells. Several investigators have suggested that there are additional receptors specific for oxidized LDL, but characterization of these alternate receptors for oxidized LDL and evaluation of their quantitative importance in uptake of oxidized LDL has been difficult because of overlapping ligand specificity with SR-AI/II. The purpose of this study was to determine the importance of SR-AI/II in the removal of modified LDL from the bloodstream in vivo. The clearance rate of oxidized LDL from plasma in normal mice was very rapid, and > 90% of injected dose was removed from the blood within 5 min. Clearance rates of oxidized LDL were equally high in SR-AI/II knockout mice, indicating that this receptor is not required for removal of oxidized LDL from plasma. Surprisingly, there was no difference in the clearance rate of acetyl LDL in wild-type and SR-AI/II knockout animals. The plasma clearance of radioiodinated acetyl LDL was almost fully blocked by a 50-fold excess of unlabeled acetyl LDL, but the latter only inhibited oxidized LDL clearance by approximately 5%. Both modified LDLs were cleared mostly by the liver, and there was no difference in the tissue distribution of modified LDL in control and knockout mice. Studies in isolated nonparenchymal liver cells showed that Kupffer cells accounted for most of the uptake of oxidized LDL. Extensively oxidized LDL and LDL modified by exposure to fatty acid peroxidation products were efficient competitors for the uptake of labeled oxidized LDL by SR-AI/II-deficient Kupffer cells, while acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors.     

Photooxidation of troglitazone, a new antidiabetic drug

Troglitazone (CS-045) is a new oral antidiabetic drug reported to be effective in insulin-resistant diabetes and to show antihypertensive effects. Photooxidation of troglitazone gave the quinone and quinone epoxide as the major final stable products. An intermediate observed by NMR spectroscopy was shown to be the hydroperoxydienone, which is moderately stable at room temperature. The rate constant of singlet oxygen quenching by troglitazone is 2.14 x 10(8) M(-1) s(-1) and the reaction rate constant in acetone-d6 is 8.64 X 10(6) M(-1) s(-1). Only the chroman ring of troglitazone reacts with and quenches singlet oxygen significantly, and its reactivity and products are analogous to those of alpha-tocopherol. The reactivity of CS-45 toward singlet oxygen is much larger than that of the related compounds lacking the chroman ring.     

The interaction of a new anti-tumour drug, KAR-2 with calmodulin

We have previously shown that chronic developmental administration of N-methyl-D-aspartate (NMDA) antagonists reduces synaptic development; however, on withdrawal from NMDA antagonism, there is a rebound period during which synaptogenesis exceeds control levels. The current research was undertaken to explore this period of withdrawal, using the noncompetitive antagonist phencyclidine (PCP), examining 2 behavioral measures in which the NMDA receptor is implicated: 1. NMDA-induced seizures, and 2. learning and memory in the Morris water maze. Using a protocol identical to that previously used to examine synaptic development, male Long-Evans rats were given 1 daily SC injection of either 10 mg/kg PCP or its physiological saline vehicle for a period of 15 days, beginning on postnatal Day 5 (P5) and ending on P20. Animals were then assessed for either sensitivity to NMDA-induced seizures on P21, P26, P36, or P56, or they were assessed for their acquisition performance and initial heading in the Morris water maze on P23, P26, P30, P38, and P75. Chronic treatment with PCP resulted in greater behavioral ratings of seizure activity after NMDA administration, observed 1 (P21), 5 (P26), and 15 (P36) days after the last injection of PCP, indicating increased sensitivity of the NMDA receptor/channel complex during this period after withdrawal from developmental NMDA antagonism. PCP-treated animals also required significantly more trials to reach criterion in the Morris water maze on P23, P26, and P30, and displayed significantly less accurate initial swim headings on all test days. The results are discussed in terms of the role of the NMDA receptor-channel complex in development and learning/memory processes.     

Convoluted cords, a new nuclear body in spermatocytes and spermatids of the rabbit

A voltammetric study of the oxidation of terbutaline has been carried out at an activated glassy carbon electrode. The compound was oxidized irreversibly at high positive potential. The response was evaluated with respect to pH, scan rate, nature of the buffer and other variables. The peak current, at about 0.8 V (versus a saturated calomel electrode), was proportional to the terbutaline concentration in the range of 8 x 10(-6)-8 x 10(-4) M in phosphate buffer pH 6.0. This method was applied, without any interferences from the excipients, to determine the drug in a tablet dosage form.     

Safety and pharmacokinetics of CS-834, a new oral carbapenem antibiotic, in healthy volunteers

CS-834, (+)-[pivaloyloxymethyl (4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(R)-5-oxopyrroli din-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate], is an ester-type oral carbapenem prodrug, and an active metabolite is R-95867, which has antibacterial activity. CS-834 was administered orally to healthy male volunteers at single doses of 50, 100, 200, and 400 mg and at a multiple dose of 150 mg three times a day for 7 days to investigate its safety and pharmacokinetic profiles. Other studies were conducted to examine the effect of food intake on the bioavailability of CS-834 and also the effect of the coadministration of probenecid on the pharmacokinetics of CS-834. In the fasting state, the concentration of R-95867 in plasma reached maximum levels from 1.1 to 1.7 h after the oral administration of CS-834, followed by a monoexponential decrease. The maximum concentrations of R-95867 in serum (C[max]s) after the administration of CS-834 at doses of 50, 100, 200, and 400 mg were 0.51, 0.97, 1.59, and 2.51 microg/ml, respectively. The half-lives (t1/2s) were almost constant, approximately 0.7 h. The areas under the concentration-time curves (AUCs) were proportional to the doses, ranging from 50 to 400 mg x h/ml. The cumulative recoveries in urine were approximately 30 to 35% until 24 h after drug administration. The C(max), AUC, t1/2, and recovery in urine were not affected by food intake. Probenecid coadministration prolonged the t1/2, and it increased the C(max) and AUC for R-95867 by approximately 1.5- and 2.1-fold, respectively. The multiple-dose study showed no change in the pharmacokinetics from those for the single doses and no drug accumulation in the body. A mild transient soft stool was observed in one volunteer in the study with a single dose of 400 mg. In the multiple-dose study, mild transient soft stools were observed in six volunteers, one volunteer had mild transient diarrhea, and one volunteer had elevated serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase levels (1.4- and 2.8-fold compared with the upper limits of normal, respectively). There were no other abnormal findings for objective symptoms or laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis.     

The effects of N-benzoyl-beta-alanine, a new nephroprotective drug, on the distribution and renal excretion of enprofylline in rats

The effects of the new nephroprotective drug N-benzoyl-beta-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2.5 mg kg-1 under three different steady-state plasma BA concentrations (100, 200 and 400 micrograms mL-1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 micrograms mL-1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 micrograms mL-1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

The value of in vitro drug activity and pharmacokinetics in predicting the effectiveness of antimycobacterial therapy: a critical review

Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.     

Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs

Rats were orally co-administered sorivudine (SRV: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), a new oral antiviral drug for herpes zoster, with the oral anticancer drug tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil) as a prodrug of 5-flourouracil (5-FU) once daily to investigate a toxicokinetic mechanism of 15 Japanese patients' deaths recently caused within a brief period by the drug interaction of these drugs. All the rats showed extremely elevated levels of 5-FU in plasma and tissues, including bone marrow and small intestine, and died within 10 days, whereas the animals given the same dose of SRV or FT alone were still alive over 20 days without any appreciable toxic symptom. Before their death, there was marked damage of bone marrow, marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported with the Japanese patients. Data obtained by in vivo and in vitro studies strongly suggested that (E)-5-(2-bromovinyl)uracil generated from SRV by gut flora was reduced in the presense of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme determining the tissue 5-FU levels, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU.     

The rabbit properdin system: I. Identification of a new factor and purification of rabbit properdin

Pure preparations of rabbit properdin were obtained from rabbit serum by ion-exchange chromatography. These preparations functioned as properdin when they were measured with the zymosan assay or with a serum reagent selectively depleted of properdin by a specific immunoabsorbent. Properdin in these preparations was in its activated state. A new serum factor was required to measure properdin activity when purified preparations of rabbit properdin were tested with the zymosan assay. This factor was designated as ZBP, or zymosan-binding protein. ZBP appeared to be distinct from known components of the alternative complement pathway and the classical complement system, and it did not appear to be an immunoglobulin.     

The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro

Recent literature continues to promote the early use of disease-modifying antirheumatic drugs (DMARDs), especially the less toxic agents such as hydroxychloroquine. Reports of combination DMARD treatments have been disappointing, and careful attention must be paid to clinical trial design if the efficacy of combination therapies is to be established. Methotrexate retains its prominent role, and its mechanism of action has been the subject of many reports; its toxicity remains the most common reason for treatment termination. Guidelines for monitoring hepatic toxicity of methotrexate have been published and may help reduce the need for invasive biopsy procedures. Significant risk factors for methotrexate pulmonary toxicity remain difficult to identify. Large placebo-controlled studies of both sulfasalazine and hydroxychloroquine have been reported and have demonstrated the efficacy of these agents in the treatment of early rheumatoid arthritis. Awareness of drug-toxicity profiles is important for physicians who prescribe these agents.     

Acute toxicity of tedisamil, a new potassium channel blocking drug

The acute intravenous toxicity of tedisamil, a new potassium channel blocker, was assessed by infusing it at various rates (1.5 to 10 mg/kg/min.) to ventilated or spontaneously breathing rats subjected to blockade of their peripheral somatic and autonomic nervous systems. The lethal doses for ventilated rats (including pithed animals) were 2-3 times higher than those for spontaneously breathing animals. In spontaneously breathing rats death appeared to be due to respiratory depression which was possibly of central origin since the lethality of tedisamil was not markedly altered by vagotomy, bilateral carotid artery ligation, nor by autonomic nervous system blockade. On the other hand, in all of the artificially ventilated groups, death occurred at higher doses and was related to direct cardiac actions, possibly involving blockade of cardiac potassium and sodium channels. The cardiovascular responses to infusions of tedisamil included tachyarrhythmias, bradycardia, blood pressure changes, increased QRS width and Q-T interval duration. Arrhythmias occurred at sublethal doses and were eliminated by autonomic blockade and pithing. However, the bradycardia, ECG and blood pressure changes induced by tedisamil infusions were unaltered by the various treatments. Thus tedisamil may induce arrhythmias by actions on the autonomic system.