Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects

BACKGROUND & AIMS: Proton pump inhibitors administered twice daily do not provide complete nocturnal acid suppression. Acid breakthrough, or decrease in intragastric pH to <4 for an hour or longer, occurs in three quarters of normal subjects and patients at night. We compared the effect of a third dose of omeprazole at bedtime with that of a dose of ranitidine at bedtime on residual nocturnal acid secretion in patients receiving omeprazole twice daily. METHODS: Twelve volunteers underwent overnight intragastric pH monitoring after 7 days of treatment with omeprazole, 20 mg twice daily, followed by different treatment supplements at bedtime: placebo; additional omeprazole, 20 mg; ranitidine, 150 mg; and ranitidine, 300 mg. RESULTS: Additional omeprazole at bedtime reduced the percentage of time with intragastric pH of <4 from 48% to 31% (P < 0.005) compared with omeprazole twice daily with placebo at bedtime. Ranitidine at bedtime reduced this parameter more, 5% with 150 mg and 6% with 300 mg (P <0.01 vs. omeprazole twice daily plus bedtime). Results for percentage of time with intragastric pH <3 were similar. Eleven subjects had acid breakthrough with placebo at bedtime; 7 with omeprazole at bedtime (P = NS); 4 with ranitidine, 150 mg at bedtime; and 3 with ranitidine, 300 mg at bedtime (P < 0. 05, ranitidine vs. placebo). CONCLUSIONS: Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related.     

Localization of putative elements of 5''-region of human tyrosine aminotransferase gene mediating its expression by glucocorticoids

The purpose of this study was to determine the pharmacokinetics and absolute bioavailability of cisapride after intravenous (i.v.) and intragastric (i.g.) administration in healthy, adult horses. Five animals received single doses of 0.1 mg/kg, 0.2 mg/kg and 0.4 mg/kg cisapride by the i.g. route in an open, randomized fashion on different occasions separated by a washout period of at least 48 h. Four of these horses were also given a single i.v. dose of 0.1 mg/kg cisapride. Jugular venous blood was collected periodically up to 24 h after dosing. Plasma cisapride concentrations were measured by high-performance liquid chromatography. There was considerable inter individual variability in pharmacokinetic parameters. The mean (SD) values for systemic clearance (CI) and steady-state volume of distribution (Vss) were 494 (43.6) mL/h/kg and 1471 (578) mL/kg, respectively. Although the rate of cisapride absorption was quite rapid, only about half the i.g. dose was absorbed systemically. The average terminal half-life (t1/2) calculated over three i.g. doses was 2.06 h and that for i.v. administration was 2.12 h. The pharmacokinetics of cisapride from 0.1 mg/kg to 0.4 mg/kg were independent of the i.g. dose.     

Administration of desmopressin in brain-dead donors and renal function in kidney recipients

BACKGROUND: Diabetes insipidus is common among brain-dead donors and may lead to decreased graft function. The use of desmopressin to limit the consequences of diabetes insipidus is controversial. We assessed the effects of desmopressin administered to brain-dead donors on early and long-term graft function in kidney recipients. METHODS: In a randomised controlled study, 97 brain-dead donors received desmopressin as 1 microg bolus every 2 h when diuresis was more than 300 mL/h (desmopressin group n=49) or no desmopressin (control group n=48). In 175 kidney recipients (controls n=89, desmopressin group n=86) we measured serum concentrations of creatinine and haemodialysis requirements to assess early renal function in the first 15 days after transplantation. We assessed long-term results of transplantation (median time 45 months) for a homogeneous subgroup of 95 recipients (48 in the desmopressin group). FINDINGS: We found no significant differences between the two groups of brain-dead donors, except for final diuresis, which was lower in the desmopressin group than among controls. Haemodialysis requirement in controls and the desmopressin group (20 vs 23%, p=0.63) and serum creatinine concentrations (decrease from 903 micromol/L to 206 micromol/L vs 814 micromol/L to 193 micromol/L, p=0.14) did not differ significantly in the first 15 days after transplantation. Long-term graft survival was similar in the two groups (88 vs 87%). INTERPRETATION: Desmopressin can be given to brain-dead donors to limit the harmful effects of diabetes insipidus without any substantial effects to graft function in recipients.     

Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson's disease

Patients with Parkinson's disease (PD) are known to experience autonomic nervous system dysfunction: this disruptive symptomatology includes urinary urgency, frequency, and nocturnal polyuria. Anticholinergic and tricyclic medications can be beneficial in controlling these urinary symptoms, but have unpleasant side effects in some patients. Desmopressin has been used to treat nocturnal polyuria successfully in a number of conditions, such as central diabetes insipidus, enuresis, and autonomic failure. The purpose of the present study was to assess the efficacy of desmopressin in patients with PD with significant nocturia. Eight patients were recruited into the study. They were first asked to establish a baseline of number of nocturnal voids; the patients were then prescribed the intranasal form of desmopressin and asked to continue to record the number of nocturnal voids. The five patients who completed the trial demonstrated clinically and statistically significant reductions in the frequency of nocturnal voids. One patient became hyponatremic and confused during desmopressin administration; his symptoms resolved soon after the desmopressin was discontinued. Two patients failed to complete the trial due to compliance problems. Thus, desmopressin appears to be a safe and effective medication for nocturnal polyuria in PD.     

Unusual accumulation of glycogen in liver parenchymal cells in a patient with anorexia nervosa

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l-1 in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg-1 plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9% saline), low dose (2.5 pmol kg-1 min-1) or high dose (5.0 pmol kg-1 kg min-1) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) micrograms min-1; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) micrograms min-1, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) micrograms min-1, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM.     

Primary pulmonary hypertension

Justification of early treatment of nocturnal enuresis is founded in the negative psychological impact on the child. In fact nocturnal enuresis delays early autonomy and socialisation by decreasing in self-esteem and self-confidence. Nocturnal enuresis classification is the preliminary step to correct therapy. Enuresis must be classified as primary (never acquired nocturnal control) or secondary (at least 6 months of dry nights). A child is also classified as having monosymptomatic enuresis if she/he experienced only night wetting and symptomatic enuresis if she/he experienced night wetting associated with diurnal voiding symptoms (urinated > or = 7 times a day, urgency, damp pants, squatting, holding the perineum, sitting on one heel). Monosymptomatic patients must be treated with desmopressin nasal spray at the daily dose of 20 micrograms at bed time. If the reduction of at least the 50% of the basal number of the wet nights is not achieved, the dosage must be increased until 40 micrograms. For patients affected by rhinitis or asthma, desmopressin is now available in tablets. In symptomatic patients desmopressin therapy must be associated to oxybutinin (5 mg x 2). Therapy interruption must be gradual with desmopressin reduction of 10 micrograms every 30 days. In symptomatic patients oxybutinin must be introduced only at bed time. The efficacy of the drugs depends on the therapy length. The highest percentage of success is obtained if the treatment is protracted for at least six months. Antidepressants are also used for nocturnal enuresis especially imipramine. The dosage varies between 0.5-1.5 mg/ kg/daily. As plasmatic levels are achieved only in 30% of treated patients, a 3-5 fold increase in suggested. Nevertheless these levels result in near toxic threshold concentration. Sporadic treatment purposes include amytriptiline, diclofenac sodicum, viloxsazine and methilphenidate if giggle incontinence is present. Non responders may be treated with alarm. If after 16 weeks of treatment no success is obtained alarm use must be interrupted.     

Negative modulation of nitric oxide production by neurotensin as a putative mechanism of the diuretic action of SR 48692 in rats

1. We investigated the effect of the non-peptide neurotensin (NT) antagonist SR 48692 on renal function in rats and the involvement of nitric oxide (NO) in the diuretic action of this compound. 2. In fed animals, SR 48692 dose-dependently (0.5 to 12.5 mg kg-1, p.o., 0.03 to 1 mg kg-1, i.p. and 0.1 to 1 microgram/rat, i.c.v.) increased urine output and urinary excretion of Na+, K+ and Cl- and reduced urine osmolality. The diuretic activity was also evident in water-deprived, fasted animals and in fasted, water-loaded rats. 3. NT (0.1 microgram/rat, i.c.v.) had no effect on urine output in fed rats, but reduced the diuretic action of SR 48692 (1 microgram/rat, i.c.v.). The opposite result was obtained in fasted, water-loaded animals: NT dose-dependently (0.01 and 0.1 microgram/rat, i.c.v.) inhibited diuresis and this effect was significantly inhibited by i.c.v. SR 48692. In this experimental condition, SR 48692 did not further increase the on-going diuresis. 4. The NO synthesis inhibitor N(1)-nitro-L-arginine methyl ester (L-NAME; 30 mg kg-1, i.p.) alone had no effect on urine output in fed rats but prevented the diuretic action of i.c.v. or i.p. SR 48692; L-arginine (1 g kg-1, i.p.) but not D-arginine (1 g kg-1, i.p.) restored the SR 48692-dependent increase in diuresis, L-NAME had no effect on furosemide-stimulated diuresis. 5. Systemically administered L-NAME or i.c.v. NT in fasted, water-loaded rats significantly reduced water diuresis but this effect was no longer seen in animals given i.p. L-arginine. Rats receiving i.c.v. NT, whose diuresis was significantly reduced, also excreted less nitrates and nitrites in urine. 6. Increased diuresis after central or systemic administration of SR 48692 to fed rats was paralleled by increased urinary excretion of nitrates and nitrites, this being consistent with peripheral enhancement of NO production after NT-receptor blockade by SR 48692. The increase in diuresis after furosemide also involved an increase of nitrates and nitrites in urine, but this effect was about half that attained with an equipotent diuretic dose of SR 48692. 7. In fed rats, the NO donor isosorbide-dinitrate, reduced systolic blood pressure (unlike SR 48692 which did not affect blood pressure) but also dose-dependently (1 and 5 mg kg-1, i.p.) stimulated urine output. 8. The overall effects of SR 48692 strongly support a link between the actions of endogenous NT, AVP and peripheral NO production in the modulation of renal excretion of water, Na+, K+ and Cl-.     

Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.     

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.     

Desmopressin versus indomethacin treatment in primary nocturnal enuresis and the role of prostaglandins

OBJECTIVES: To compare the efficacy of desmopressin and indomethacin and also determine the prostaglandin E2 (PGE2) concentrations in the patient and control groups. METHODS: Eighty-five children with primary nocturnal enuresis were followed up for a baseline period of 4 weeks, during which they recorded wet and dry nights. After this period, the patients were divided into three groups that used desmopressin, indomethacin, or placebo for 4 weeks. The dosage of desmopressin (group A, n = 31 ) was 20 microg/day and the dosage of indomethacin (group B, n = 29) was 100 mg/day. The placebo group (group C) consisted of 25 patients. We determined the serum PGE2 and urine PGE2 concentrations before and after treatment in the three groups and in a control group. RESULTS: Treatment with desmopressin and indomethacin resulted in significantly more dry nights during the 4 weeks of observation than did placebo (P <0.005). The number of dry nights was also significantly different in the desmopressin group than in the indomethacin group (P <0.01). In the total patient group, the mean serum and urine PGE2 concentrations were significantly different from the control group's serum and urine PGE2 concentrations (P <0.001). There was a significant decrease in the serum and urine PGE2 concentrations in group A and group B after the treatment period (P <0.01). CONCLUSIONS: Desmopressin and indomethacin were found to be more effective than placebo. We conclude that prostaglandins have an important role in the pathophysiology of primary nocturnal enuresis.     

Diagnosis of thoracic outlet syndrome in the emergency department

Gadodiamide at a dose of 0.1 mmol/kg was administered intravenously to 10 renal transplanted patients with stable, impaired, or slowly deteriorating renal function (serum creatinine 194-362 mumol/l). The patients were referred for contrast medium enhanced magnetic resonance imaging to rule out possible graft circulation abnormalities. The excretion of gadodiamide in urine was prolonged as compared with healthy controls. After 120 h 92% of the injected dose was excreted in urine and only 0.4% in faeces. The plasma clearance of gadodiamide was 28.6 +/- (SD) 5.5 ml/min (n = 10), and the renal clearance (0-72 h) was 26.3 ml/min. The renal clearance of 125I-iothalamate for the same time period was 27.9 +/- 5.3 ml/min. Thus, gadodiamide is eliminated by glomerular filtration also in renal transplant patients with moderately to severe impaired renal function, and gadodiamide clearance may serve as an alternative marker for the determination of the glomerular filtration rate. Serum values of creatinine and beta(2)-microglobulin and creatinine clearance were unchanged by gadodiamide and neither was the urinary enzyme excretion significantly changed. These results suggest that the renal tolerance to gadodiamide is good also in renal transplant patients with impaired renal function.     

The effect of plasma free fatty acids and long-chain triglycerides on glucose metabolism in uncomplicated falciparum malaria

To investigate the therapeutic potential of increased plasma free fatty acid (FFA) and triglyceride concentrations in hypoglycaemic patients receiving quinine, 32 untreated Thai adults with uncomplicated falciparum malaria were allocated at random to one of 4 regimens: 2 mg/kg/min dextrose infused over 60 min either alone (group A) or with a prior injection of 5000 units of heparin and simultaneous Intralipid infusion (group C), or 4 min/kg/min dextrose alone (group B) or with heparin and Intralipid (group D). Quinine (10 mg/kg) was also infused over 60 min in all cases. In patients of groups A and C, mean changes in plasma glucose concentrations from the beginning to the end of the infusion were 0.1 (SD 0.8) and 1.0 (SD 0.7) mmol/L respectively (P = 0.015). In groups B and D, plasma glucose increased by 1.8 (SD 1.2) and 2.2 (SD 0.4) mmol/L respectively (P < 0.5). Plasma FFA levels fell by approximately 50% during the infusion in groups A and B but increased by a similar percentage in groups C and D. Despite significant mean increases in plasma insulin during the infusion (from 12.2 milliunits (mu)/L in group A to 38.8 mu/L in group D), no rebound hypoglycaemia was observed in any patient during the ensuing 7 h. These data suggest that the glycaemic response to dextrose given at high rates, which match average glucose utilization in a severely ill patient with malaria, is not augmented by increased plasma FFA and long-chain triglycerides. However, this strategy increases the glycaemic efficacy of lower dextrose infusion rates and the combination could, therefore, reduce the volumes of hypertonic dextrose required to prevent hypoglycaemia in severely ill patients in whom optimal fluid balance is crucial.     

Survey of the effects of smoking in an occupational cohort study. Value and limits of a new method

The arterial wall injury associated with arterial graft implantation causes smooth muscle cells (SMCs) in the media to migrate and proliferate in the intima at the graft-artery junction resulting in anastomotic intimal hyperplasia (AIH). An important step in developing a small-diameter prosthesis may be to stimulate endothelialization and thereby inhibit AIH. In this study, we investigated the effect of coacervated and crosslinked alpha-elastin on proliferation of SMCs and endothelial cells (ECs) in vitro. Coacervation is an important step in the conversion of proelastin to make an elastin fiber in vivo. SMCs and ECs were prepared from porcine aortic media and endothelium, respectively. SMCs and ECs (three to five passages, 4 x 10[4] cells/well) were seeded onto 12 well plates, coated and crosslinked with 0 or 10 mg/mL of coacervated alpha-elastin. After the 1st, 2nd, or 3rd day of cultivation, proliferation was assayed by scintillation counting of [3H]-thymidine incorporation. For the 4th day only, 0, 0.1, 1, 10 mg/mL concentration of coacervated alpha-elastin was coated and crosslinked. SMC proliferation (1st, 2nd day: p<0.005; 3rd, 4th day: p<0.0001) was significantly inhibited over time and dose dependently, eg, 0.1 mg/mL (45.7+/-2.3%: % of control p<0.005), 1 mg/mL (5.9+/-0.7%, p<0.0005), 10 mg/mL (2.8+/-0.4%, p<0.0005). EC proliferation was inhibited over time by 10 mg/mL of coacervated alpha-elastin (2nd, 3rd day: p<0.005; 4th day: p<0.0001), but proliferation (132.8+/-9.9%: % of control p=NS) was stimulated by 0.1 mg/mL of coacervated alpha-elastin. These results suggest that coating and crosslinking a coacervated alpha-elastin into the structure of arterial prosthesis may inhibit AIH and stimulate endothelialization.     

Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus

The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.     

Phase I and pharmacologic study of topotecan in patients with impaired renal function

PURPOSE: To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS: Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS: In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION: Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions.     

Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential usefulness in the diagnosis of Cushing's disease

Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with Cushing's disease led to the present study of the prevalence of this phenomenon in 58 patients with otherwise incontrovertible evidence of Cushing's disease. Because as many as 23% of these patients manifested this phenomenon, we investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients and 16 controls. The data showed invariable suppression of plasma ACTH to < or = 10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same times in 14/14 patients with active Cushing's disease, including 3 patients whose cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7 patients with intermittent hypercortisolism. Occasional variations in plasma cortisol elevations after the oral dose require that plasma cortisol concentration be monitored at 60 min after the oral hydrocortisone dose, because the present evidence supports the validity of the conclusion that a plasma ACTH concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of ACTH suppressibility by cortisol would be worthwhile, to confirm its potential value in facilitating positive diagnosis of Cushing's disease when dexamethasone suppressibility seems misleading.     

Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry

PURPOSE: This study assesses the value of the urinary methylmalonic acid (MMA) assay by gas chromatography mass spectrometry as a screening procedure for detection of cobalamin (Cbl) deficiency and estimates the prevalence of undetected Cbl deficiency in elderly populations. SUBJECTS AND METHODS: A total of 809 elderly individuals over age 65 were screened using random spot urine specimens from 4 different sites: a health fair, retirement apartments, a hospital-based elderly assessment center, and a nursing home. Follow-up tests included serum total Cbl, serum MMA, and normalization of urinary and serum MMA levels with Cbl intramuscular (IM) therapy. RESULTS: The prevalence of elevated urinary MMA varied across population groups, from 3.0% in elderly visiting a health fair to 5.1% in elderly residing in retirement apartments. Follow-up on 35 of 36 subjects with elevated urinary MMA levels showed that 18 had low serum total Cbl (less than 180 pg/mL at Hospital 1 or less than 200 pg/mL at Hospital 2), 12 had low-normal Cbl (180 or 200 pg/mL to 350 pg/mL), and 5 had normal Cbl. Of the 12 subjects with low-normal Cbl on retesting, further assessment was performed in 7, and all 7 of these subjects had evidence of Cbl deficiency. Cbl IM therapy was initiated for 23 subjects; 16 were seen for follow-up and all had normal urinary MMA. CONCLUSION: The relatively high prevalence of undetected Cbl deficiency identified in the seniors warrants additional studies of elderly populations. The sensitivity, convenience, and noninvasive nature of the urinary MMA assay by gas chromatography mass spectrometry make it a practical screening test.     

cAMP analogues downregulate the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in human bone marrow stromal cells in vitro

STUDY OBJECTIVE: To determine the neuromuscular blocking effect and recovery profile of cisatracurium besylate in children after administration of a bolus dose that was twice the estimated dose required to produce 95% of the maximum effect (2 x ED95; 0.08 mg/kg) followed by an infusion during halothane-nitrous oxide anesthesia. STUDY DESIGN: Open-label study. SETTING: Teaching hospital. PATIENTS: 30 male and female (ASA physical status I and II) patients, 2 to 10 years of age, scheduled for elective surgery of low to moderate risk. INTERVENTIONS: After induction of general anesthesia, patients received cisatracurium 0.08 mg/kg administered over 5 to 10 seconds. For surgical procedures requiring neuromuscular block for at least 60 minutes, a second bolus dose of cisatracurium 0.02 mg/kg was administered after the first response to a train-of-four stimuli (T1) recovered to 25% of baseline. When T1 was 5% of baseline after the second dose, a 3 microg/kg/min infusion of cisatracurium was initiated and titrated to maintain 89% to 99% block for the duration of the surgery. For procedures requiring neuromuscular block of less than 60 minutes, one or more maintenance doses of 0.02 mg/kg cisatracurium were administered when T1 was 25% of baseline after the preceding dose. In 10 patients, recovery was facilitated with edrophonium 1.0 mg/kg administered when T1 was 26% to 48% of the final baseline. MEASUREMENTS AND MAIN RESULTS: Evoked muscular response at the adductor pollicis was measured by electromyography. With 0.08 mg/kg, onset time (mean +/- SEM) was 4.1 +/- 0.4 minutes, and clinically effective duration was 27.3 +/- 0.9 minutes. Mean 5% to 95% and 25% to 75% recovery indices were 28.4 +/- 2. 7 minutes and 11.2 +/- 0.8 minutes, respectively. The mean infusion rate necessary to maintain 89% to 99% T1 suppression for 17 to 145 minutes was 1.7 microg/kg/min. After termination of infusion, the mean 5% to 95% and 25% to 75% recovery indices were similar to those after a single bolus dose, and time to 95% recovery was 30.4 +/- 3.0 minutes. After administration of edrophonium, full recovery (T4:T1 > or = 70%) occurred in 1.5 +/- 0.4 minutes. No clinically significant changes in heart rate or blood pressure were noted during the first 5 minutes after administration of cisatracurium 0.08 mg/kg. CONCLUSIONS: Cisatracurium provided maximal neuromuscular block, cardiovascular stability, and predictable recovery at the doses tested. In view of this finding, cisatracurium should be a useful intermediate-duration neuromuscular blocking drug for children during general anesthesia.     

Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9% NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 +/- 0.04 ml/min vs 1.45 +/- 0.18 ml/min in vehicle-treated rats, P < 0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 +/- 0.34 ml/60 min and 3.39 +/- 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.     

The dobutamine-dopamine combination versus amrinone in congestive heart failure with a marked edematogenic sign complicated by functional kidney failure. A comparison between 2 different models of inotropic stimulation and diuresis potentiation

BACKGROUND: We evaluated the diuretic output in patients with decompensated chronic heart failure (CHF), previously treated by i.v. infusion with dobutamine and dopamine (dob-dop) or with amrinone (amr). Our target was to identify the possible discrepancies in urinary output perhaps linked to the different type of inotropic stimulation in the two subsets. METHODS: Adjunctive therapy with dob-dop or amr was chosen because the administration of diuretics only, without cardiac support, as tested in previous hospitalizations, had been demonstrated to produce unfavourable results, mainly expressed by finding of a low output syndrome in 50% of cases or more. The administration of i.v. infusion was maintained during 17 hours (1000 min approximatively), and included infusion in separate pumps of the two amines, dobutamine at dose of 5 micrograms/kg/min and dopamine at dose of 2.8 micrograms/kg/min or, alternatively, i.v. infusion of amr, administered at dose of 7 micrograms/kg/min. Infusion volumes were similar in the two subsets. The two subsets were homogeneous relatively to renal impairment, i.e. to the parameters (urinary Na, U/P creatinine, U/P urea, urinary osmolality) we fixed as markers idoneous to demonstrate the occurrence of organic renal damage (acute tubular necrosis). RESULTS: The diuresis was recovered in all 24 patients, and the urine volume resulted more pronounced in the subset attributed to the dob-dop at both the 8th and the 17th hour readings. We found no harmful alterations in HR and AP, whereas renal function parameters have been shown to enhance in both the dob-dop and amr arms. The diuretic effectiveness of the SIEV obtained by catecholamine implementation exercised a synergistic, favourable effect on diuresis, renal flow, glomerular filtration rate, and sodium post-proximal delivery. Amr resulted less effective then dob-dop simultaneous administration relatively to the diuretic effect. No remarkable differences were found in the two subsets as regards the heart rate, whereas a decrease in arterial pressure was found after amr. A persistent shift towards a condition of chronic renal failure, was identified in 4/24 patients, the two groups despite of the prolonged treatment at optimized doses: no remarkable side effects were reported. CONCLUSIONS: Thus, the selective effect upon renal hemodynamics, as exercised by dob-dop infusion low doses of dop, together with the enhanced renal output due to dob, has been shown to be more effective than amr influence: thus, the catecholamine therapeutical approach has been demonstrated to possess the best effectiveness in excitation of diuresis, among the CHF oliguric patients.