Effect of ranitidine on intragastric pH in clinically normal neonatal foals

OBJECTIVE: To determine intragastric pH in newborn foals and to examine the effect of i.v. or oral administration of an H2-receptor antagonist on intragastric pH. DESIGN: Prospective controlled study. ANIMALS: 6 healthy mixed-breed neonatal foals. PROCEDURE: Intragastric pH was measured, using an antimony electrode. Foals were monitored on days 2, 4, and 6 after birth, and each received 3 treatments. The pH was recorded for 4 hours before treatment and for 10 hours after ranitidine administration (2 mg/kg [0.91 mg/lb] of body weight, i.v.; 6.6 mg/kg [3 mg/lb], PO) or 20 hours after corn syrup administration. Mean and median pH and percentage of time pH was > or = 4 were calculated. RESULTS: Mean intragastric pH significantly increased for 5 hours after i.v. administration of ranitidine, compared with baseline data. Percentage of time intragastric pH was > or = 4 increased significantly for 4 hours after ranitidine administration, and median pH increased significantly for hours 2 to 4 after administration. Oral administration of ranitidine significantly increased mean and median pH for hours 2 to 8 after administration and percentage of time pH was > or = 4 for hours 2 to 7 after administration. CLINICAL IMPLICATIONS: Neonatal foals have highly acidic gastric fluid. Intravenous or oral administration of ranitidine significantly increased intragastric pH for 4 and 8 hours, respectively. Suckling affected intragastric pH and underscored the need for frequent feeding of neonatal foals.     

Use of backrest elevation in critical care: a pilot study

BACKGROUND: Use of lower backrest positions occurs frequently and is a factor in the development of ventilator-associated pneumonia. OBJECTIVES: To determine the usual bed elevation and backrest position in a medical intensive care unit and their relationship to hemodynamic status and enteral feeding. METHODS: Data were collected in a 12-bed medical respiratory intensive care unit for 2 months. A protractor was used to measure the elevation of the head of the bed. Hemodynamic status was defined by systolic, diastolic, and mean arterial blood pressure measurements retrieved from each patient's flow sheet. RESULTS: The sample included 347 measurements of 52 patients. Mean backrest elevation was 22.9 degrees, and 86% of patients were supine. Backrest position differed significantly (P = .005) among nursing shifts (days, evenings, nights) but not for systolic (r = -0.04, P = .49), diastolic (r = 0.01, P = .83), or mean arterial blood pressure (r = -0.01, P = .84). Backrest elevation did not differ significantly between patients who were receiving enteral feedings and patients who were not (P = .23) or between patients receiving intermittent versus continuous nutrition (P = .22). CONCLUSIONS: Use of higher levels of backrest elevation (> or = 30 degrees) is minimal and is not related to use of enteral feeding or to hemodynamic status. The rationale for using lower backrest positions for critically ill patients may be based on convenience, the patient's comfort, or usual patterns in the unit. However, the dangers of supine positioning and its relationship to aspiration and ventilator-associated pneumonia should not be minimized.     

A mammographic evaluation of the morphostructural variations of the breast during hormone-replacement therapy in the postmenopause

OBJECTIVE: To compare i.v. ketorolac with i.v. prochlorperazine as the initial treatment of migraine headaches in the ED. METHODS: A prospective, double-blind comparison study was performed, using a convenience sample of 64 patients suffering from migraine headaches presenting to the ED at a tertiary care university teaching hospital. Patients were randomly assigned to receive either 10 mg of prochlorperazine i.v. or 30 mg of ketorolac i.v.. Patients scored the severity of their headaches using a 10-cm visual analog pain scale. An initial mark was made on the scale at the time of entry into the study and later another mark was made on a new unmarked pain scale 1 hour after medication administration. Changes in pain scores within each treatment group and between groups were analyzed using the Wilcoxon rank sum test. RESULTS: Prior to treatment, the patients assigned to receive prochlorperazine had a median score of 9.2 cm (mean +/- SD pain score of 8.3 cm +/- 2.1 cm), while the patients receiving ketorolac had a median score of 9.0 (mean pain score of 8.4 cm +/- 1.7 cm). There was no significant difference between the pain scores of the participants in the 2 groups prior to treatment (p = 0.80). One hour after medication administration, the patients in the prochlorperazine group had a median score of 0.5 cm (mean 2.1 +/- 3.2 cm), while those patients receiving ketorolac had a median pain score of 3.9 (mean 4.0 +/- 3.3 cm). The decrease in pain score was significant for both groups of patients (p = 0.0001). The change in pain score for the patients in the prochlorperazine group (median 7.1) was significantly greater than the change in pain score for the patients in the ketorolac group (median 4.0; p = 0.04). CONCLUSION: Although both drugs were associated with a significant reduction in pain scores, benefit over a placebo agent was not tested. Furthermore, the patients who received prochlorperazine i.v. for migraine headaches had a statistically significant greater decrease in their pain scores than did those receiving ketorolac i.v.     

Randomized phase II noncomparative trial of oral and intravenous doxifluridine plus levo-leucovorin in untreated patients with advanced colorectal carcinoma

BACKGROUND: Doxifluridine (5-dFUR) is a fluoropyrimidine derivative that has been shown to be active on a variety of solid tumors. The clinical use of intravenous (i.v.) 5-dFUR as a bolus injection or short term infusion has been limited because of its unpredictable severe neurotoxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administered orally. METHODS: This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and September 1994. A total of 130 previously untreated patients with locally advanced or metastatic colorectal carcinoma were randomized to receive oral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m2 twice daily for 4 days every 12 days (arm A) or i.v. 1-leucovorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m2 for 5 days every 21 days (arm B). RESULTS: The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the most common site. A median of 7 oral courses (range, 1-15) and 5 intravenous courses (range, 1-9) were administered. Intent-to-treat analysis rate of the randomized patients revealed a response rate of 15% (95% confidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated, and the response rates, according to standard analysis, were respectively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to treatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (range, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarrhea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the patients in both arms; no severe neurotoxicity was reported. CONCLUSIONS: 5-dFUR with l-leucovorin, administered either orally or intravenously, produces response rates that are similar to those offered by the regimens containing 5-FU that are usually used to treat advanced colorectal carcinoma. This study documents the good tolerance of the i.v. schedule administered as a 1-hour infusion; furthermore, oral administration seems to be promising and feasible as a home treatment.     

Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery

We analyzed morphine clearance values in infants receiving the drug by continuous i.v. infusion for analgesia after surgery, because we found lower steady-state morphine concentrations than we expected from our previous studies. Infants received morphine after a loading dose of 0.05 mg/kg and continuous infusion calculated to reach a steady-state concentration of 20 ng/mL. Blood was sampled twice on Postoperative Day 1 at times separated by at least 2 h, and morphine and morphine-6-glucuronide (M-6-G) concentrations were determined by high-performance liquid chromatography. Clearance of morphine was calculated as infusion rate divided by the steady-state morphine concentration. Morphine given to 26 infants by continuous i.v. infusion after major noncardiac surgery has rapidly increasing clearance values, from a median value of 9.2 mL x min(-1) x kg(-1) in infants 1-7 days old, 25.3 in infants 31-90 days old, and 31.0 in infants 91-180 days old to 48.9 in infants 180-380 days old. Adult clearance values are reached by 1 mo of age, more quickly than in infants of the same age previously studied who received morphine after cardiac surgeries. M-6-G was measured in all infants. The ratio of M-6-G to morphine concentrations was 1.9-2.1 in these infants, which is lower than ratios reported in older infants or adults by others, but higher than those reported in newborns. Infants with normal cardiovascular systems undergoing surgery clear morphine more efficiently than infants of the same age undergoing cardiac surgery. Implications: Morphine removal from the body is slow in newborns but increases to reach adult values in the first months of life. Calculating the clearance of morphine from blood samples drawn during continuous i.v. infusions after surgery shows that this maturation occurs more quickly in infants undergoing noncardiac surgery (by 1-3 mo of age) than in those receiving morphine after cardiac surgery (by 6-12 mo of age).     

Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine

In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(-/-) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(-/-) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2- and 6-fold higher in mdr1a(-/-) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(-/-) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(-/-) mice. Biliary excretion was not significantly different in wt and mdr1a(-/-) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(-/-) mice. We conclude that P-glycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.     

Pharmacokinetics of cefepime and comparison with those of ceftiofur in horses

OBJECTIVE: To determine pharmacokinetics of i.v., i.m., and oral administration of cefepime in horses and to compare pharmacokinetics of i.m. administration of cefepime with those of ceftiofur sodium. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 3 doses of cefepime (11 mg/kg of body weight, PO; 2.2 mg/kg, i.v.; and 2.2 mg/kg, i.m.) and 1 dose of ceftiofur (2.2 mg/kg, i.m.). Two horses also received L-arginine, p.o. and i.v., at doses identical to those contained in the cefepime dihydrochloride-L-arginine preparations previously administered. Blood samples were collected for 24 hours after administration of cefepime or ceftiofur and were assayed for cefepime and ceftiofur concentrations. RESULTS: Pharmacokinetic analysis of disposition data indicated that i.v. administration data were best described by a 2-compartment open model, whereas i.m. administration data were best described by a 1-compartment absorption model. Median elimination half-life and volume of distribution after i.v. administration of cefepime were 125.7 minutes and 225 ml/kg, respectively. After i.m. administration of cefepime, mean maximal plasma concentration of (8.13 microg/ml) was reached at a mean time of 80 minutes. Absorption of cefepime after i.m. administration was complete, with a median bioavailability of 1.11. Intramuscular administration of ceftiofur resulted in similar mean maximal plasma concentration (7.98 microg/ml) and mean time to this concentration (82 minutes). Cefepime was not detected in samples collected after oral administration. Adverse effects consisting principally of gastrointestinal disturbances were observed after oral and i.m. administration of cefepime and after 1 i.m. administration of ceftiofur. CONCLUSIONS AND CLINICAL RELEVANCE: Cefepime, administered i.v. or i.m. at a dosage of 2.2 mg/kg, every 8 hours is likely to provide effective antibacterial therapy for cefepime-sensitive organisms in horses. Further studies are needed to evaluate adverse effects on the gastrointestinal tract.     

General pharmacology of S 15261, a new concept for treatment of diabetes

The new compound S 15261 (CAS 159978-02-6) is the I-isomer of 3-[2-[2-[4-[2-(alpha-Fluorenylacetylamino)ethyl]benzoyloxy]ethylam ino]-1- methoxyethyl]trifluoromethylbenzene. The general synthetic pathway used for the preparation of S 15261 and related esters is given in this paper. This compound was selected for its promising therapeutical action on blood glucose, insulin resistance and associated risk factors present in patients with non-insulin-dependent Diabetes mellitus (NIDDM). The general pharmacological profile of S 15261 was investigated. The data given in this paper show that S 15261 has presented a very low acute toxicity (lethal dose in mice greater than 1600 mg/kg orally) and did not induce significant behavioural changes in rats. A poor anorectic effects was observed after acute administration in rats. In guinea pigs S 15261 acutely induced a significant and dose-dependent hypoglycaemic effect (ED25 = 40 mg/kg orally). Biogenic amines and their metabolites in different structures of the brain were only slightly affected after acute administration of S 15261. Chronic administration of this compound (2.5 mg/kg bid for 14 days p.o.) did not cause significant alterations in the brain amines content, with the exception of an increase of serotonin (19%) in the striatum, a result not confirmed by the dose-effect study (from 1 mg/kg to 12.5 mg/kg bid for 14 days p.o.). In vitro binding assays with 31 different receptors did not show significant affinity of S 15261 for any of them. The rat arterial blood pressure was decreased (12 mmHg) after acute (25 mg/kg i.v.) or repeated administration (2.5 mg/kg bid for 14 days p.o.) without any dose-dependent effect. We therefore conclude that S 15261 may not have significant adverse effect even at doses higher than the pharmacological effective range of doses. Although the mechanism of action of this new class of compounds was not fully understood, other pharmacological data suggest that S 15261 acts at both the liver (intraportal infusion) and skeletal muscle (microdialysis studies) at least in part to enhance insulin sensitivity. For all these activities S 15261 may be useful to treat patients with NIDDM or insulin resistance known to be the major risk for onset of NIDDM.     

Pharmacokinetics and bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 MG) after repeated administration in healthy volunteers

The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3-4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the "once a day" formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.     

Diazinon toxicokinetics, tissue distribution and anticholinesterase activity in the rat

The toxicokinetics, tissue distribution, and anticholinesterase (antiChE) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after i.v. administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following i.v. and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailability was found to be low (35.5%). Hepatic extraction ratios after i.v. administration of 5 or 10 mg/kg were 54.8% and 47.7%, respectively, suggesting that low systemic oral bioavailability can be explained by a first-pass effect in the liver. Diazinon was found to be approximately 89% protein-bound in plasma within the concentration range 0.4-30 ppm. The highest concentration of diazinon after i.v. administration was found in the kidneys, when comparing to liver, kidney, brain. Both red blood cell (RBC) acetylcholinesterase (AChE) and plasma ChE activities were inhibited rapidly (44% and 17% at 10 min, and 36% and 13% min for i.v. and oral administration, respectively), but inhibition of RBC AChE was greater than that of plasma ChE.     

Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling [3H]histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with [125I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by approximately 100% histamine turnover rate and steady state level of tele-methylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H3-receptor agonist induced enhancement of water consumption in rats with and ID50 of 0.09 +/- 0.04 mg/kg, i.p. In cats, ciproxifan (0.15-2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.     

Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers

OBJECTIVE: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor, was studied in six healthy, male volunteers aged 19-34 years, followed for 8 h after each drug administration. METHODS: For i.v. administration the subjects received 4 micrograms dDAVP. For intestinal administration 500 micrograms dDAVP was administered directly, in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and aprotinin was administered enterally at the constant rate of 5 ml.min-1 for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement of lipase, chymotrypsin and pH every 30 min for 5 h. RESULTS: The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified. After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml.min.kg-1. The mean bioavailability after duodenal administration of dDAVP+ aprotinin was 0.46% compared with 0.09% after duodenal administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of an enzyme inhibitor.     

Pharmacokinetics of gentamicin following single-dose parenteral administration to goats

The disposition kinetics of parenterally administered gentamicin (5 mg kg-1) has been studied in Gaddi goats. The serum concentration-time profile was described by bi-exponential and mono-exponential equations following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration with elimination half-life values of 0.96 +/- 0.09, 2.37 +/- 0.47 and 3.56 +/- 0.39 h, respectively. The apparent volume of distribution following i.v. administration (Vdarea: 0.26 +/- 0.041 kg-1) reflected limited extracellular distribution of the drug. The bioavailability was higher following i.m. administration (96.3%) compared to s.c. (76.9%). In view of the significantly longer biological half-life and larger area under the curve values, the s.c. route may be preferred. It is concluded that a suitable and practical dosage recommendation for gentamicin in goats would be 3.35 mg kg-1 body weight given s.c. at 12 h intervals.     

Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers

Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.     

Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition

Glutamine is normally an abundant amino acid in the body. It has many important metabolic roles, which may protect or promote tissue integrity and enhance the immune system. Low plasma and tissue levels of glutamine in the critically ill suggest that demand may exceed endogenous supply. A relative deficiency of glutamine could compromise recovery, resulting in prolonged illness and an increase in late mortality, morbidity, and consequently hospital costs. Using a prospective block-randomized, double-blind treatment study design, we tested whether a glutamine-containing enteral feed compared with an isonitrogenous, isoenergetic control feed would influence outcome. The study endpoints were morbidity, mortality, and hospital cost at 6 mo postintervention. In one general intensive care unit (ICU), to ensure consistency of management policies, 78 critically ill adult patients with Acute Physiological and Chronic Health Evaluation (APACHE) II score of 11 and greater and who were considered able to tolerate introduction of enteral nutrition were studied. Fifty patients successfully received enteral nutrition (26 glutamine, 24 control). There was no mortality difference between those patients receiving glutamine-containing enteral feed and the controls. However, there was a significant reduction in the median postintervention ICU and hospital patient costs in the glutamine recipients $23,000 versus $30,900 in the control patients (P = 0.036). For patients given glutamine there was a reduced cost per survivor of 30%. We conclude that in critically ill ICU patients enteral feeds containing glutamine have significant hospital cost benefits.     

Continuous infusion of loop diuretics in the critically ill: a review of the literature

OBJECTIVES: a) To present the pharmacodynamic concepts behind the administration of loop diuretics via continuous infusion; b) to review the clinical trials and reports in critically ill patients that have described this method of drug delivery; and c) to discuss the data. DATA SOURCES: Review of MEDLINE and International Pharmaceutical Abstracts from 1966 to the present. STUDY SELECTION: Study design was not a factor in selecting literature for this review. All studies, case reports, and case series describing infusion of a loop diuretic are included. DATA EXTRACTION: Cited literature was found in peer-reviewed clinical or basic science journals. DATA SYNTHESIS: There is a pharmacodynamic basis for the use of a controlled infusion of the loop diuretics in critically ill patients requiring extensive diuresis. Animal and human volunteer studies have demonstrated a clear improvement in efficiency of diuresis by controlled infusion Clinical studies in critically ill patients have demonstrated an improved diuretic response with a controlled infusion. Adverse effects appear to be minimal, and the amount of drug required for effect is less than the required amount for bolus administration. CONCLUSION: Administration of loop diuretics by continuous intravenous infusion may improve diuresis in critically ill patients who require prompt, controllable diuresis, or who demonstrate "diuretic tolerance" to conventional administration regimens. Despite few, well-designed studies using this method of administration in clinical practice, pharmacodynamic concepts support continuous infusion over bolus administration, including decreased dosage requirements, improved diuretic response and few adverse effects.     

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

ZD9331 is a novel, potent thymidylate synthase (TS) inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.     

The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760

The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)