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1.
J Clin Pharmacol ; 48(6): 726-33, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18441333

ABSTRACT

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.


Subject(s)
Electrocardiography , HIV Integrase Inhibitors/adverse effects , Pyrrolidinones/adverse effects , Adult , Anti-Infective Agents/adverse effects , Aza Compounds/adverse effects , Cross-Over Studies , Double-Blind Method , Female , Fluoroquinolones , HIV Integrase Inhibitors/pharmacokinetics , Humans , Male , Middle Aged , Moxifloxacin , Pyrrolidinones/pharmacokinetics , Quinolines/adverse effects , Raltegravir Potassium , Time Factors
2.
Xenobiotica ; 34(4): 379-89, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15268982

ABSTRACT

1. The disposition and metabolism of ertapenem, a carbapenem antibiotic, was examined in rat, monkey and man. Sprague-Dawley rats and Rhesus monkeys were given, by intravenous administration, radiolabelled doses of ertapenem (60 and 30 mg kg(-1), respectively), and healthy normal volunteers received a single fixed dose of 1000 mg. Urine and faeces were collected for determination of total radioactivity. 2. In healthy volunteers, [14C]ertapenem was eliminated by a combination of hydrolytic metabolism to a beta-lactam ring-opened derivative and renal excretion of unchanged drug. Approximately equal amounts were excreted as a beta-lactam ring-opened metabolite and unchanged drug (36.7 and 37.5% of dose, respectively). A secondary amide hydrolysis product accounted for about 1% of the dose in man. About 10% of the administered radioactivity was recovered in faeces, which suggested that a minor fraction underwent biliary and/or intestinal excretion. 3. In animals, a greater fraction of the dose was eliminated via metabolism; excretion of unchanged drug accounted for 17 and 5% of dose in rats and monkeys, respectively. In monkeys, the beta-lactam ring-opened and amide hydrolysis metabolites accounted for 74.8 and 7.59% of the dose, respectively, whereas in rats, these metabolites accounted for 31.9 and 20% of dose, respectively. 4. In vitro studies with fresh rat tissue homogenates indicated that lung and kidney were the primary organs involved in mediating formation of the beta-lactam ring-opened metabolite. The specific inhibitor of dehydropeptidase-I, cilastatin, inhibited the in vivo and in vitro metabolism of ertapenem in rats, which suggested strongly that the hydrolysis of ertapenem in lung and kidney was mediated by this enzyme.


Subject(s)
Feces/chemistry , Lactams/pharmacokinetics , Adult , Animals , Carbapenems/blood , Carbapenems/pharmacokinetics , Carbapenems/urine , Carbon Radioisotopes/pharmacokinetics , Ertapenem , Female , Humans , Lactams/blood , Lactams/urine , Macaca mulatta , Male , Metabolic Clearance Rate , Middle Aged , Organ Specificity , Radioisotope Dilution Technique , Radiopharmaceuticals/pharmacokinetics , Rats , Species Specificity , Tissue Distribution , beta-Lactams
3.
Antimicrob Agents Chemother ; 48(2): 521-4, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14742204

ABSTRACT

Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC(0- infinity ) of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC(0- infinity ) of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects ( approximately 5 to 11%) was generally greater than that in young adults ( approximately 5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.


Subject(s)
Carbapenems/pharmacokinetics , Lactams/pharmacokinetics , Adult , Aged , Area Under Curve , Creatinine/blood , Ertapenem , Female , Half-Life , Humans , Injections, Intravenous , Male , Spectrophotometry, Ultraviolet , beta-Lactams
4.
Antimicrob Agents Chemother ; 46(11): 3506-11, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12384357

ABSTRACT

Ertapenem (INVANZ) is a new once-a-day parenteral beta-lactam antimicrobial shown to be effective as a single agent for treatment of various community-acquired and mixed infections. The single- and multiple-dose pharmacokinetics of ertapenem at doses up to 3 g were examined in healthy young men and women volunteers. Plasma and urine samples collected were analyzed using reversed-phase high-performance liquid chromatography with UV detection. Ertapenem is highly bound to plasma protein. The protein binding changes from approximately 95% bound at concentrations of <50 micro g/ml to approximately 92% bound at concentrations of 150 micro g/ml (concentration at the end of a 30-min infusion following the 1-g dose). The nonlinear protein binding of ertapenem resulted in a slightly less than dose proportional increase in the area under the curve from 0 h to infinity (AUC(0- infinity )) of total ertapenem. The single-dose AUC(0- infinity ) of unbound ertapenem was nearly dose proportional over the dose range of 0.5 to 2 g. The mean concentration of ertapenem in plasma ranged from approximately 145 to 175 micro g/ml at the end of a 30-min infusion, from approximately 30 to 34 micro g/ml at 6 h, and from approximately 9 to 11 micro g/ml at 12 h. The mean plasma t(1/2) ranged from 3.8 to 4.4 h. About 45% of the plasma clearance (CL(P)) was via renal clearance. The remainder of the CL(P) was primarily via the formation of the beta-lactam ring-opened metabolite that was excreted in urine. There were no clinically significant differences between the pharmacokinetics of ertapenem in men and women. Ertapenem does not accumulate after multiple once-daily dosing.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Lactams , Adult , Area Under Curve , Blood Proteins/metabolism , Dose-Response Relationship, Drug , Double-Blind Method , Ertapenem , Female , Half-Life , Humans , Injections, Intravenous , Male , Protein Binding , Sex Characteristics , Spectrophotometry, Ultraviolet , beta-Lactams
5.
J Clin Pharmacol ; 39(6): 636-42, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10354968

ABSTRACT

The effect of multiple doses of indinavir on the pharmacokinetics of a single dose of theophylline was investigated in 16 healthy male subjects using a randomized, double-blind, placebo-controlled, parallel-group study design. On days 1 and 7, all of the subjects received a single oral 250 mg dose of theophylline. From days 2 to 7, the subjects received orally administered 800 mg doses of indinavir or a matched placebo every 8 hours. On day 7, theophylline and indinavir (or a placebo) were coadministered. The geometric mean AUC(0-24 h) of theophylline increased 18% when coadministered with indinavir compared to when theophylline was administered alone. This small increase in AUC(0-24 h), although considered statistically significant, did not meet the prespecified criterion for clinical significance. The geometric mean Cmax of theophylline, when coadministered with indinavir, was within 8% of theophylline when administered alone. The mean tmax (+/- SD) value for theophylline, when coadministered with indinavir (0.9 +/- 0.5 h), was comparable to that observed for theophylline alone (1.0 +/- 0.5 h). In conclusion, the administration of multiple doses of indinavir followed by a single dose of theophylline did not appear to result in a clinically significant pharmacokinetic interaction for theophylline.


Subject(s)
Anti-HIV Agents/pharmacology , Bronchodilator Agents/pharmacokinetics , Indinavir/pharmacology , Theophylline/pharmacokinetics , Administration, Oral , Adolescent , Adult , Anti-HIV Agents/adverse effects , Area Under Curve , Bronchodilator Agents/adverse effects , Dizziness/chemically induced , Double-Blind Method , Drug Interactions , Humans , Indinavir/adverse effects , Lip Diseases/chemically induced , Male , Middle Aged , Theophylline/adverse effects
6.
Pediatrics ; 102(1 Pt 1): 101-9, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9651421

ABSTRACT

BACKGROUND: Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. METHODS: Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. RESULTS: Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. CONCLUSIONS: Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.


Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Indinavir/therapeutic use , Adolescent , Adult , Biological Availability , CD4 Lymphocyte Count , Capsules , Child , Child, Preschool , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , HIV/drug effects , HIV Infections/blood , HIV Infections/virology , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/pharmacokinetics , Humans , Indinavir/adverse effects , Indinavir/pharmacokinetics , Infant , Lamivudine/adverse effects , Lamivudine/pharmacokinetics , Lamivudine/therapeutic use , Male , Suspensions , Viral Load , Virus Replication/drug effects , Zidovudine/adverse effects , Zidovudine/pharmacokinetics , Zidovudine/therapeutic use
7.
J Clin Pharmacol ; 37(4): 279-84, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9115052

ABSTRACT

The objective of the study was to assess the extent of systemic exposure of retinoic acid metabolites after excessive application of 0.1% isotretinoin cream in patients with photodamaged skin. This was a single-center, open-label, noncomparative, multiple-dose study of isotretinoin cream. Eighteen female patients with photodamaged skin received a 10 g topical application of isotretinoin cream once daily to a surface area of approximately 2,300 cm2 for 42 days. The patients were not allowed to have high vitamin A-containing foods, vitamin A supplements, or concomitant medications during the entire study period. Plasma levels of four retinoic acids (isotretinoin, tretinoin, 4-oxo-isotretinoin, and 4-oxo-tretinoin) were evaluated after 42 days of isotretinoin application and compared with baseline (pretreatment) levels. The mean area under the curve (AUC) in plasma increased by 48% (+/-SE 9.2) and 77% (+/-13) from the 24-hour pretreatment baseline level for isotretinoin and 4-oxo-isotretinoin, respectively, after treatment with excessive amounts of isotretinoin cream, suggesting systemic absorption of isotretinoin cream. This increase in systemic exposure of retinoic acids was less than that reported earlier after the U.S. recommended daily allowance of 5,000 i.u. of vitamin A supplementation (isotretinoin 141 +/- 19% and 4-oxo-isotretinoin 171 +/- 27%). The minimal systemic availability of isotretinoin cream compared with the U.S. recommended daily allowance for vitamin A supplements provides reasonable evidence for lack of its potential teratogenic risk.


Subject(s)
Isotretinoin/pharmacokinetics , Keratolytic Agents/pharmacokinetics , Teratogens/pharmacokinetics , Administration, Cutaneous , Adult , Area Under Curve , Female , Humans , Isotretinoin/therapeutic use , Keratolytic Agents/therapeutic use , Middle Aged , Skin Absorption , Skin Diseases/drug therapy
8.
J Clin Pharmacol ; 36(9): 799-808, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8889900

ABSTRACT

These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4-oxo-tretinoin, and 4-oxo-isotretinoin in samples collected during the studies were analyzed using a high-performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model-independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4-oxo-tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration-time curve (AUC) for isotretinoin and 4-oxo-isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 +/- 53% and 171 +/- 77% from baseline in the 24-hour AUCs of isotretinoin and 4-oxo-isotretinoin, respectively. Dose-related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.


Subject(s)
Food , Keratolytic Agents/pharmacokinetics , Retinoids/pharmacokinetics , Vitamin A/administration & dosage , Adult , Area Under Curve , Drug Interactions , Female , Food Analysis , Food-Drug Interactions , Humans , Isotretinoin/pharmacokinetics , Metabolic Clearance Rate , Retinoids/blood , Tretinoin/pharmacokinetics , Vitamin A/analysis
9.
J Assoc Physicians India ; 41(8): 500-2, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8294352

ABSTRACT

Acute mountain sickness (AMS) is an important cause of morbidity and mortality following acute exposure to high altitude. Several clinical variables were evaluated during the 1990 Trans-Kalindi Exploration to extreme altitude (5949 m) in 10 healthy adult lowlanders (age 31.7 +/- 6.4 yrs) who undertook a relatively rapid ascent from sea level to 5949 m with short periods of acclimatisation at 4393 m, 4898 m and 5700 m. 40% of the subjects had definite AMS. Only one subject had features of early cerebral oedema at 4393 m and had to be brought down temporarily to 3878 m. All subjects completed the trek without needing medication. Proper acclimatisation was characterised by absence of significant symptoms of AMS above 4500 m, absence of sustained tachycardia, fall in daily positive fluid balance from 1.7 +/- 0.9 (sea level) liters to 0.7 +/- 0.3 litres (at 5700 m) (p < 0.05), increase in 24 hours urinary sodium excretion from 174 +/- 78 mmol to 344 +/- 145 mmol (p < 0.01) and an increase in the ratio of urinary excretion of sodium and potassium from 3.1 (sea level) to 3.6 (5700 m). We conclude that the incidence of AMS at extreme altitude is similar to that at lower altitude. Reasonable acclimatisation is possible during the climb to extreme altitude.


Subject(s)
Altitude Sickness/physiopathology , Mountaineering , Acclimatization , Adult , Female , Humans , Male
10.
J Mol Cell Cardiol ; 18(1): 13-22, 1986 Jan.
Article in English | MEDLINE | ID: mdl-3005595

ABSTRACT

Activities of several adenosine metabolizing enzymes were examined in capillary preparations isolated from rabbit ventricle. Vmax and Km values for 5'-nucleotidase were 2.3 nmol/min/mg and 10 microM, respectively. For adenosine deaminase the corresponding values were 7.8 nmol/min/mg and 32 microM. S-adenosyl-homocysteine hydrolase, which forms adenosine by the hydrolysis of S-adenosylhomo-cysteine, was also present (Vmax, 0.07 nmol/min/mg; Km, 0.81 microM), as were adenosine kinase (Vmax, 0.2 nmol/min/mg; Km, 0.52 microM) and purine nucleoside phosphorylase (Vmax, 13.8 nmol/min/mg; Km, 96 microM). These enzymes were also present in microvessels (capillaries and arterioles) purified from rabbit brain. Activities of several enzymes, especially 5'-nucleotidase and adenosine deaminase, were much lower in myocytes isolated from rabbit ventricle. The study provides evidence that endothelial cells of the microvasculature from heart and brain are capable of activity forming and degrading adenosine. It is possible that adenosine formed by these cells may contribute to the local regulation of blood flow.


Subject(s)
Adenosine/metabolism , Capillaries/metabolism , Cerebrovascular Circulation , Coronary Vessels/metabolism , 5'-Nucleotidase , Adenosine Deaminase/metabolism , Animals , Heart Ventricles , Inosine/metabolism , Kinetics , Nucleotidases/metabolism , Rabbits , Rats , S-Adenosylhomocysteine/metabolism
11.
Microvasc Res ; 26(2): 157-69, 1983 Sep.
Article in English | MEDLINE | ID: mdl-6312274

ABSTRACT

Microvessels (capillaries) were isolated in pure form from rabbit ventricle by a process which involved fine mincing of the tissue, repeated incubation with collagenase to effect cell dispersal, passage of the suspended cells over a column of glass beads, and finally concentration of the capillary fraction on a step-wise sucrose gradient. Adenylate cyclase in the capillary preparation was stimulated by beta adrenergic agonists in a potency order which suggested coupling to a beta 2 subtype adrenergic receptor. Catecholamine-stimulated activity was antagonized by methoxamine, but this did not seem to be mediated through alpha adrenergic receptor activation, since it was not reversed by the alpha adrenergic antagonist phentolamine. Adenylate cyclase was stimulated by adenosine and several adenosine analogs in a potency order which suggested enzyme coupling to a stimulatory A2 receptor. Prostaglandins were also effective stimulators of enzyme activity, those of the E and A series being more potent than members of the F series. It is possible that these agents may exert their physiological actions on the microvasculature via cyclic AMP formed in response to activation of adenylate cyclase.


Subject(s)
Adenosine/pharmacology , Adenylyl Cyclases/metabolism , Catecholamines/pharmacology , Coronary Vessels/drug effects , Prostaglandins/pharmacology , Animals , Capillaries/drug effects , Capillaries/enzymology , Capillary Permeability/drug effects , Coronary Vessels/enzymology , Cyclic AMP/metabolism , Male , Rabbits , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, beta/drug effects , Stimulation, Chemical
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