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Biomedical subjects

S K Gupta

Publications and source records attributed to S K Gupta.

At least 235 records · Page 13Linked to original sources
PubMed1999

Quantitative characterization of therapeutic index: application of mixed-effects modeling to evaluate oxybutynin dose-efficacy and dose-side effect relationships.

BACKGROUND: Describing a therapeutic index for a drug is important for evaluating safe and effective dosage regimens. Therapeutic index can be evaluated as the relative position of the dose-efficacy and the dose-side effect curves. Oxybutynin XL (Ditropan XL), a once-daily oral controlled-release formulation for oxybutynin chloride, is being developed. Oxybutynin XL efficacy and side-effect data obtained from two parallel-group, randomized, controlled clinical trials were modeled to evaluate the therapeutic index. METHODS: A nonlinear mixed-effects model was used to characterize the oxybutynin dose-efficacy and dose-dry mouth relationship. Weekly urge urinary incontinence episodes, the primary efficacy variable, is a discrete variable (counts) with only non-negative integer values and was therefore modeled as a Poisson variable. The probability of dry mouth severity (the most frequently reported side effect), assessed on a categorical four-point scale, was modeled with a proportional odds model. In the modeling process, it was assumed that the time effect was the same for the active and placebo treatments and that the drug effect was additive. RESULTS AND CONCLUSIONS: The urge urinary incontinence episodes declined log-linearly, and no significant difference was observed between the two formulations. However, there was a trend toward higher efficacy with oxybutynin XL than with immediate-release oxybutynin at the same dose in one study. Dose-dry mouth analysis showed that the probability of dry mouth with an increasing dose was significantly lower with oxybutynin XL than with immediate-release oxybutynin in the second study, and a similar trend was observed in the first study. By combining the dose-urge urinary incontinence and dose-dry mouth relationship, a wider therapeutic index was predicted for oxybutynin XL than for immediate-release oxybutynin.

Adult↗
PubMed1999

Reactive oxygen intermediates and reactive nitrogen intermediates in copper intrauterine device users.

The mechanism of action of copper in copper intrauterine devices (Cu IUD) as an antimicrobial agent is not well understood. Copper and iron are supposed to be responsible for release of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), which are very active in the presence of infection. The copper in a copper IUD could be responsible for limiting pelvic inflammatory disease. The present study was composed of 20 IUD seekers in whom ROI and RNI were studied before insertion of Cu IUD and then at 1, 4, and 12 weeks afterward. ROI showed a rise after insertion, whereas RNI showed a steady decline. Hence, it is presumed that the rise in ROI could be responsible for both the bactericidal effect of Cu IUD and also for the fall in RNI.

Chromogenic Compounds↗
PubMed1999

Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates.

OBJECTIVES: (1) To assess the feasibility and tolerability of the therapeutic transdermal fentanyl system (TTS-fentanyl) by using a clinical protocol developed for children with cancer pain. (2) To estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. METHODS: The drug was administered in open-label fashion; and measures of analgesia, side effects, and skin changes were obtained for a minimum of 2 doses (6 treatment days). Blood specimens were analyzed for plasma fentanyl concentrations. The pharmacokinetics of TTS-fentanyl were estimated by using a mixed effect modeling approach. RESULTS: Treatment was well tolerated. Ten of the 11 patients who completed the 2 doses continued treatment with TTS-fentanyl. The duration of treatment ranged from 6 to 275 days. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 microg/h patch. Compared with published pharmacokinetic data from adults, the mean clearance and volume of distribution of transdermal fentanyl were the same, but the variability was less. CONCLUSIONS: Treatment of children with TTS-fentanyl is feasible and well tolerated and yields fentanyl pharmacokinetic parameter estimates similar to those for adults. A larger study is required to confirm these findings and further test the clinical protocol.

Administration, Cutaneous↗
PubMed1999

Tethered cord syndrome in adults.

BACKGROUND: The tethered cord syndrome (TCS) is usually diagnosed in childhood and its symptomatic onset in adult life is not common. In the present study, we analyzed the data of patients who presented with TCS in adulthood with the aim of studying the clinical spectrum and management strategies. CLINICAL MATERIAL: Over a 5-year period, 18 adult patients (more than 18 years of age) with TCS were investigated with MRI and were operated on. Patients with adult TCS could be divided into two groups. Group 1 included patients who were asymptomatic in childhood and presented for the first time in adult life (10 patients). The second group was comprised of patients with preexisting static skeletal/neurological deformities who presented in adult life with new or progressive symptoms (eight patients). Eleven patients had cutaneous stigmata, 15 had motor or sensory deficit, nine had back/leg pain, eight had leg atrophy, and six had sphincter disturbances. The most frequent MRI finding was a low lying cord with an intradural and/or extradural lipoma. The cord was detethered surgically and the tethering lesion excised. Pain was usually relieved after surgery (8 out of 9), but only a few patients (2 out of 6) had improvement of sphincter dysfunction. CONCLUSIONS: The late presentation of TCS is possibly related to the degree of tethering and the cumulative effect of repeated microtrauma during flexion and extension. Adult patients with persistent back/leg pain and/or neurological or skeletal deformities should be investigated with MRI to establish an early diagnosis. Surgery should be performed in all adult patients with TCS, once the diagnosis is established.

Adult↗
PubMed1999

Reproducible fentanyl doses delivered intermittently at different time intervals from an electrotransport system.

The electrotransport transdermal fentanyl system (ET [fentanyl]), uses a small electrical current to enhance delivery of fentanyl to systemic circulation. Intermittent doses can be administered by periodic application of the current. The purpose of this study was to compare the effects of the frequency of intermittent drug delivery by ET (fentanyl) and compare the drug delivery to systemic circulation by ET (fentanyl) with intravenous administration. The topical safety was also determined for the ET (fentanyl) system. Nine adult male volunteers completed this three-treatment, randomized, 24-h, crossover study. ET (fentanyl) treatments with 200 microA direct current applied for 30 min at frequent (hourly) or infrequent (4-hourly) intervals over a 24-h period were compared. Also, the drug delivery to systemic circulation from ET (fentanyl) was compared with intravenous fentanyl 75 microg infused over 30 min every 4 h over a 24-hour period. The mean serum fentanyl concentration achieved with the hourly ET (fentanyl) regimen was higher than that for the 4-hourly ET (fentanyl) regimen as expected from the higher frequency of drug doses. The amount of fentanyl delivered estimated per dose from the ET (fentanyl) system using the iv fentanyl treatment as the reference was similar for the two ET regimens throughout the dosing period. This indicates consistent drug delivery regardless of the frequency of ET dosing. The majority of subjects reported either no, or barely perceptible, erythema 24 h after removal of the system.

Administration, Cutaneous↗
PubMed1999

Effect of transdermal iontophoresis codelivery of hydrocortisone on metoclopramide pharmacokinetics and skin-induced reactions in human subjects.

The effects of transdermal iontophoresis (IP) codelivery of hydrocortisone (HC) on metoclopramide hydrochloride (MCP) pharmacokinetics and on skin-induced reactions were evaluated in a randomized, crossover clinical study. MCP, an antiemetic, low molecular weight, cationic drug intended for systemic delivery, was delivered from the anode of IP systems at a constant current of 100 microA/cm(2). HC, a neutral endogenous antiinflammatory agent, was codelivered from the same electrode, primarily by electroosmotic processes. Each subject (n = 7) wore two identical IP systems (MCP alone or MCP plus HC), each supplying 500 microA, one on each upper arm for 4 h. One week later, each subject repeated the procedure with the alternate type of MCP system. HC did not change the pharmacokinetics of MCP: There were no statistically significant differences in MCP plasma concentrations, half-life, area under the curve (AUC), or rate of absorption between the two treatment groups. However, HC significantly decreased erythema and edema scores produced by the IP of MCP. In both groups, a steady-state MCP flux of about 100 microg/(cm(2) x h) was achieved after only 1 h of transport, and input rate dropped dramatically immediately after removal of the system. In vitro, HC flux through human epidermis from an MCP plus HC formulation was 2.8 +/- 1.1 microg/(cm(2) x h) after 4 h transport at 100 microA/cm(2), suggesting negligible systemic exposure to hydrocortisone. These data indicate that MCP input rate and its clearance from the skin are unaltered by HC and that the codelivery of HC by IP is an effective strategy for inhibition of local reactions resulting from the transdermal delivery of drugs.

Administration, Cutaneous↗
PubMed1999

Visual outcomes after cataract surgery and cataract surgical coverage in India.

Visual outcomes of 2369 cataract operated persons(3655 eyes) across seven major Indian states were assessed in 1998. This is the largest ever study over the past decade in the country. 9.54 per cent of the examined population had undergone operation for cataract in one or both eyes. Intra-capsular cataract extraction was the commonest surgical modality adopted (91.62%). Intraocular lens implants resulted in better visual outcomes with 71.4 per cent of such patients achieving a good visual outcome (> or = 6/18 in operated eyes). Visual outcome was also good if ICCE operated patients were provided good quality aphakic spectacles. There were no gender differentials in surgical uptake rates. The risk of poor postsurgical visual outcome was strongly associated by type of surgery (Adjusted OR for ICCE-2.78; 95% CI: 1.41-5.49) and the non-availability or poor quality aphakic spectacles (Adjusted OR for poor/no spectacles 4.59-95% CI: 3.53-5.97). Duration since surgery and the source of surgery did not influence visual outcomes. Half the cataract blind remained unoperated in the study population.

Aged↗
PubMed1999

Spinal cord injury without radiographic abnormality in adults.

Spinal cord injury without fractures or bony malalignment on either plain radiographs or computed tomography (SCIWORA) is most commonly found in the paediatric age group. In recent years, magnetic resonance imaging (MRI) has been used to evaluate these patients. The present communication describes SCIWORA in 15 adult patients investigated by MRI. Of the 151 patients with spinal cord injury in 1 year, 15 adult patients had cervical SCIWORA. All patients were evaluated by MRI. The age ranged from 20 - 60 years. Eleven patients had partial cord injury, two had a complete cord syndrome while two had a central cord syndrome. MRI demonstrated an intervertebral disc prolapse in six patients, intramedullary haematoma/contusion in four and cord oedema in four patients. One patient had multiple disc prolapses and associated intramedullary haematoma. Patients with disc prolapse were operated upon and all showed neurological improvement. The rest of the patients were managed conservatively. There was mild improvement in patients with intramedullary haematomas while those with cord oedema alone showed moderate recovery. The pathogenesis of adult SCIWORA is possibly different from that in paediatric age group. Most of the patients with SCIWORA show some abnormality on MR imaging. MRI should therefore be done in all patients with spinal cord injury for diagnostic and prognostic purposes.

Adult↗
PubMed1999

Pharmacokinetic and pharmacodynamic characterization of OROS and immediate-release amitriptyline.

AIMS: To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS and IR treatments, and to correlate them with anticholinergic side-effects. METHODS: The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-way crossover feasibility study, the subjects received a single 75 mg OROS tablet, three 25 mg IR tablets administered every 8 h, or 3x25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject-rated drowsiness and dry mouth were measured on a continuous scale during each treatment period. RESULTS: Following dosing with OROS (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml-1 ) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml-1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration. CONCLUSIONS: The bioavailability of OROS (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled-release formulation of amitriptyline may be appropriate for single daily administration.

Adult↗
PubMed1999

Reduction of redundant neural network activation during the performance of a task: a functional model applied to problem-solving strategies.

Problem-solving is explained by various paradigms. For example, epistemological paradigms state that, when the task is novel, and pursued of one's free will, problem-solving occurs in discontinuous, discernable phases. It is then also a microdevelopmental process, i.e. involves the construction of knowledge through qualitatively different stages of thought. Quantitative methods are used to focus on the redundancy of function as well as the concept of selective activation of the brains's neural network during the performance of a task. In this model, the following are identified: (a) performance circuits: (i) NP, no performance; (ii) LP, low performance; (iii) MP, medium performance; (iv) HP, high performance; and (v) VHR, very high performance; (b) task performance groups: (i) NOU, no outline used; (serves as a control); (ii) OU, outline used; (iii) MOU, modified outline used; (iv) QMOU, qualitatively and quantitatively modified outline used. An example of a distribution that one obtains is (for the efficiency of activation of the HP): QMOU:MOU:OU. NOU is in the ratio of: 400:100:50:5 (out of 10(3) trials). The subject is hence educated as to the mechanism of various strategies that he may use in everyday problem-solving.

Brain↗
PubMed1999

Childhood-onset primary open angle glaucoma in a Canadian kindred: clinical and molecular genetic features.

OBJECTIVE: To describe the clinical features and identify the molecular etiology of childhood-onset primary open angle glaucoma (POAG) in a Canadian kindred. METHODS: Members of a Canadian Caucasian family with POAG were examined and DNA obtained. Single-strand conformation polymorphism analysis was performed using reported primers from exon 3 of the myocilin gene. A single-stranded conformation polymorphism was characterized by polymerase chain reaction-based sequencing. RESULTS: Two affected half-sibs had onset of severe glaucoma at age 3 and 9. Their mother had lost vision in one eye from glaucoma by age 17. All three affected subjects had undergone bilateral glaucoma filtering surgery. Both fathers were unaffected. A single-stranded conformation polymorphism was identified in the mother and the two affected daughters and was absent in one father. A single base change from C-->T at nucleotide position 1109 was identified in the affected members of the family by direct sequencing. This mutation, which causes a nonconservative amino acid change (Pro370Leu), was not found on 192 normal chromosomes from Caucasian individuals. CONCLUSION: We report a Canadian family with childhood-onset, severe POAG due to a mutation in the myocilin gene.

Adult↗
PubMed1999

Comparative studies on topical lomefloxacin and ciprofloxacin on ocular kinetic and experimental corneal ulcer.

Fluoroquinolones are antimicrobial agents that have a broad spectrum of activity and that are widely used against many of the ocular pathogens responsible for conjunctivitis, blepharitis, corneal ulcers, etc. The aim of our study was to compare the ocular pharmacokinetics of ciprofloxacin (0.3% w/v) and lomefloxacin (0.3% w/v) by HPLC after a single application of 50 microl topically. The study was also extended to compare their efficacy in experimentally-induced corneal ulcers. In ocular kinetic studies, lomefloxacin showed nearly 10 times more ocular bioavailability in aqueous humor as compared to ciprofloxacin. Lomefloxacin showed a Cmax of 1.62 microg/ml at the Tmax of 1 hr whereas ciprofloxacin showed a Cmax of 102.8 ngs/ml at the Tmax of 1 hr. Lomefloxacin was found to have significant efficacy in the healing of Staphylococcus aureus-induced corneal ulcers and associated lesions. Moreover, aqueous formulation oflomefloxacin showed a good compatibility at neutral pH. The results of our study indicate that a suitable treatment regimen with lomefloxacin (0.3%) therapy could be an excellent therapeutic alternative over ciprofloxacin in bacterial keratitis.

Administration, Topical↗
PubMed1999

Clinical applications of technetium Tc 99m hexamethyl propylene amine oxime leukocyte scan in children with inflammatory bowel disease.

BACKGROUND: Labeled leukocyte imaging is a helpful diagnostic tool in the detection of inflammation and sepsis. The technetium Tc 99m hexamethyl propylene amine oxime (99mTc HMPAO)-labeled leukocyte scan has been found to be more sensitive than the Indium-111 labeled leukocyte scan in detecting inflammatory bowel disease, with reported sensitivities of 95% to 100%. Experience with the 99mTc HMPAO-labeled leukocyte scan was examined and its clinical applications evaluated in the immediate treatment of patients with inflammatory bowel disease. METHODS: A retrospective chart review was undertaken that included pediatric patients who underwent 99mTc HMPAO-labeled leukocyte scan at the James Whitcomb Riley Hospital for Children. The disease activity of patients with inflammatory bowel disease was assessed. The leukocyte scan was performed according to the manufacturer's specifications, and images were obtained 30 minutes and 2 hours after administration of the radiopharmaceutical. RESULTS: During the period of July 1996 through November 1997, 41 scans were performed in 35 patients. Twenty-nine patients had histologically proven inflammatory bowel disease: 24 with Crohn's disease, 4 with ulcerative colitis, and 1 with indeterminate colitis. Active inflammatory bowel disease was suspected in 24 patients when the leukocyte scan was performed. Twenty of the 24 patients (83% sensitivity) had abnormal findings in leukocyte scans that prompted more aggressive management in 15 (75%). Six of the 15 who were receiving maximum medical therapy underwent surgical resection of severely affected bowel segments, and medical treatment was intensified in the other 9. The remaining 5 patients were receiving optimal medical therapy, instituted at their recent visit, and did not require further medication adjustments. Four of the 24 patients with active inflammatory bowel disease had normal leukocyte scans (17% false-negative rate), 3 of whom were receiving corticosteroid therapy at the time the scans were performed. All of the 11 patients in whom inflammatory bowel disease was in remission and 6 patients who did not have inflammatory bowel disease had normal findings in leukocyte scans (100% specificity). CONCLUSIONS: Although a tissue diagnosis is still recommended, obtained during upper and lower gastrointestinal endoscopic examinations, and contrast radiography of the small bowel for the initial work-up of patients with suspected inflammatory bowel disease, the 99mTc HMPAO-labeled leukocyte scan is a safe and useful diagnostic adjunct for subsequent evaluation of patients known to have inflammatory bowel disease. The results of 99mTc HMPAO-labeled leukocyte scans directly influenced treatment of 75% of the study patients with active inflammatory bowel disease, which included the decision to refer patients for surgical intervention.

Adolescent↗
PubMed1999

Disaccharidase activities in children: normal values and comparison based on symptoms and histologic changes.

BACKGROUND: The relationship between symptoms, intestinal mucosal histology, and disaccharidase activities is not well defined. An analysis of disaccharidase activities was performed in children grouped by age, symptoms, and intestinal mucosal histology and normal values established. METHODS: Disaccharidase activities and histology of 246 endoscopically obtained duodenal biopsies in 232 patients (121 girls; age range, 0.08-17 years; mean, 5.9 years) in a 3-year period were reviewed. Patients were divided into two groups based on absence (group 1; n = 142) or presence (group 2; n = 90) of diarrhea and were subdivided by age into, less than 24 months of age and 24 months of age or more. Histologic changes within groups were classified as (A) normal, (B) mild, or (C) moderate to severe based on villus height abnormalities. A questionnaire was sent to 34 patients with hypolactasia to assess the efficacy of lactose avoidance and/or lactase supplementation. RESULTS: All group 1 patients had normal findings in analysis of mucosal specimens, and their disaccharidase activities showed normal values because they had no diarrhea. The geometric means (95% confidence interval) in children aged less than 24 months are (in micromoles of substrate hydrolyzed per minute at 37 degrees C per gram protein) (units [U]) lactase, 36.7 (13.4-100.4); maltase, 178.5 (88.9-356.3); palatinase, 12.7 (3.8-41.5); and sucrase 60.0 (24.0-148.1). In children 24 months of age or more, the values are 23.2 (3.9-108.1), 167.6 (78.8-355.9), 12.7 (4.9-32.9), and 51.0 (20.5-126.0), respectively. Only lactase activity decreased with age (p < 0.05). No differences in disaccharidase activities were noted in patients with and without diarrhea if the mucosal histology was normal (group 1A vs. 2A). In patients with diarrhea, values were commensurate with the degree of mucosal injury, especially in the older group. Twenty-two of 27 patients (81%) who responded to the questionnaire had benefited from lactase supplementation and/or lactose avoidance. CONCLUSIONS: We have established normal values for disaccharidase activities in the pediatric population. Although the disaccharidase activities correlate more with degree of intestinal mucosal injury than with symptoms, their activities are difficult to predict accurately based on these criteria. If required, disaccharidase activities should be measured biochemically.

Adolescent↗
PubMed1999

A new clinical perspective of corneal dystrophies through molecular genetics.

In the past 2 years, significant advances have been made in the genetics of corneal dystrophies. Genetic heterogeneity (one disease condition caused by single mutations in any one of multiple genes) and phenotypic diversity (many disease conditions caused by mutations in a single gene) are common emerging themes. Genetic heterogeneity in Meesmann corneal dystrophy was established with the identification of two causative genes, keratins 3 and 12, that encode cytoskeletal proteins. Conversely, mutations in a single gene, keratoepithelin, were found to cause several distinct corneal dystrophies affecting the Bowman layer and the stroma. We present a novel preliminary classification of corneal dystrophies based on molecular etiology. This classification may be useful in understanding the pathogenesis of corneal dystrophies and in developing new strategies to treat these dystrophies.

Cornea↗
PubMed1999

Epidemiological evaluation of recurrent stomatitis, nitrates in drinking water, and cytochrome b5 reductase activity.

OBJECTIVE: Our aim was to examine a possible correlation between drinking water nitrate concentration, recurrent stomatitis, and cytochrome b5 reductase activity. Dietary nitrate can form nitrite in vivo. This can cause methemoglobinemia in the red blood cells. Cytochrome b5 reductase is an enzyme in the red blood cells that reduces methemoglobin back to hemoglobin. METHODS: Five areas were selected in the State of Rajasthan, India, having drinking water nitrate concentration (as nitrate) of 26, 45, 95, 222, and 459 mg of NO3/L. House schedules were prepared in these areas in accordance with a statistically designed protocol. We selected 193 age- and weight-matched persons, representing 10% of the total population in each of these areas. Detailed history was taken for recurrent stomatitis, medical examination was conducted, and blood samples were taken to ascertain cytochrome b5 reductase activity in the selected population. Collected data were statistically analyzed to ascertain a relationship between nitrate concentration, cytochrome b5 reductase activity, and percent stomatitis, using Microsoft Excel software. RESULTS: This study suggests that there is a significant interdependence between drinking water nitrate concentration, cytochrome b5 reductase activity, and recurrent stomatitis. CONCLUSION: Increased cytochrome b5 reductase activity primarily induced by the presence of high nitrate concentration in drinking water could be the cause for recurrent stomatitis.

Cytochrome Reductases↗
PubMed1999

Pharmacokinetics and absolute bioavailability of ribavirin in healthy volunteers as determined by stable-isotope methodology.

Ribavirin has recently been demonstrated to have efficacy in combination with alpha interferon for treatment of relapsed hepatitis C. The marked improvement in the response rate after treatment with the combination regimen (10-fold higher versus that from monotherapy with alpha interferon) highlights the importance of determining the absolute bioavailability of ribavirin as a first step in beginning to investigate the pharmacodynamics of the combination. The objective of this study was to determine the absolute bioavailability of ribavirin with an intravenous formulation containing ribavirin labeled with the stable isotope (13)C(3) ((13)C(3)-ribavirin) and unlabeled oral ribavirin. Six healthy volunteers received 150 mg of intravenous (13)C(3)-ribavirin followed 1 h later by a 400-mg oral dose of ribavirin. Samples of blood and urine were collected up to 169 h postdosing. Concentrations of (13)C(3)-ribavirin and unlabeled ribavirin were determined by a high-performance liquid chromatography tandem mass spectrometric method. All plasma and urine data were comodeled for labeled and unlabeled ribavirin by using both the two- and three-compartment models in the program ADAPT II. A three-compartment model was chosen for the pharmacokinetic analysis with the Akaike Information Criterion. The mean maximum concentrations of drug in plasma for intravenous and oral ribavirin were 4,187 and 638 ng/ml, respectively. The mean bioavailability was 51.8% +/- 21.8%, and the mean gamma-phase half-life was 37.0 +/- 14. 2 h. The mean renal clearance, metabolic clearance, and volume of distribution of the central compartment were 6.94 liters/h, 18.1 liters/h, and 17.8 liters, respectively. The use of the stable-isotope methodology has provided the best estimate of the absolute bioavailability of ribavirin that is currently available, as there was neither a period bias nor a washout effect to confound the data. The study demonstrated that the mean bioavailability for a 400-mg dose of ribavirin was 52%, which is higher than that previously reported in other investigations.

Adult↗