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Biomedical subjects

S W Sanders

Publications and source records attributed to S W Sanders.

At least 37 records · Page 2Linked to original sources
PubMed1991

Day-night and individual differences in response to constant-rate ranitidine infusion.

Twelve ulcer patients with inactive disease received constant-rate infusions of ranitidine, in doses of 6.25 and 10.0 mg/hr, during separate 24-h spans. Gastric pH and serum ranitidine concentrations were monitored. Serum ranitidine concentrations did not vary significantly after attainment of steady-state. For the group, gastric acidity was controlled above pH 4 during the day; however, at night, when gastric acid secretion was greatest under placebo conditions, ranitidine less effectively controlled gastric pH. There was individual variation in response to ranitidine. Patients (8/12) evidencing control of gastric acidity (pH greater than or equal to 4) for at least 16 h when infused with ranitidine (6.25 mg/h) were considered responders. Those (4/12) not so well controlled were designated poor responders. With parenteral infusion of 6.25, as well as 10.0 mg/h ranitidine, responders evidenced a relatively high 24-h mean pH and only minor day-night variation in gastric acidity. In contrast, poor responders were characterized by a low 24-h mean pH and high-amplitude circadian variation in gastric acidity. Poor responders evidenced statistically significant (p less than 0.05) lower gastric pH responses to parenteral infusions than did responders. A similar, significant difference between the two groups was observed when the percentage of time that gastric pH was maintained below 4 was considered. Differences between responders and poor responders to ranitidine infusion are unknown. Since Zollinger-Ellison syndrome patients were not included in the study, observed differences in drug response cannot be ascribed to hypersecretion of gastric acid.

Adult↗
PubMed1991

Effect of basal gastric acid secretion on the pharmacodynamics of ranitidine.

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured approximately every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 +/- 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 +/- 1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. +/- 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion--as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC50) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC50 and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.

Adult↗
PubMed1991

Intragastric pH and pharmacokinetics of intravenous ranitidine during sinusoidal and constant-rate infusions.

Six patients with healed duodenal ulcer completed two treatment periods with continuous i.v. infusion ranitidine. A 25-mg i.v. bolus was followed by a constant infusion at 6.25 mg/h or a sinusoidal infusion with infusion rates ranging from 3.125 to 9.375 mg/h. The sinusoidal infusion rate was designed to match the previously observed circadian changes in basal acid secretion. The peak infusion rate occurred at 19:30 h. A pharmacokinetic method was designed to predict the resultant plasma concentrations of ranitidine. Intragastric pH and plasma ranitidine concentration data were fit to a cosine function to evaluate circadian and ultradian rhythms. Plasma concentrations during the sinusoidal infusion exhibited a circadian rhythm according to model predictions. Cosinor analyses of the mean ranitidine plasma concentration data showed a mesor concentration of 237 ng/mL and amplitude of 76 ng/mL (coefficient of determination [CD] = 0.98). The acrophase in plasma concentration occurred at 2223 h, a delay of approximately 2.9 hours from the peak in the infusion rate. The constant-rate infusion resulted in a mean plasma concentration of 222 +/- 32 ng/mL. The 24-h mean intragastric pH values for the sinusoidal and constant regimens were 5.4 and 5.1, respectively (p = 0.170). The intragastric pH during the constant-rate infusion exhibited a significant circadian rhythm (CD = 0.52). The minimum pH (bathy-phase) occurred at 2031 h. No circadian rhythm was present during the sinusoidal-rate infusion (CD = 0.08). At the approximate time of the peak basal acid secretion, between 21:00 hours and midnight, the mean pH for the sinusoidal infusion was 5.77 versus 4.5 for the constant-rate infusion (p = 0.112). Sinusoidal infusions or alternate methods of increased doses at the times of peak acid output may improve around-the-clock control of intragastric pH.

Adult↗
PubMed1989

Pharmacodynamics of intravenous ranitidine after bolus and continuous infusion in patients with healed duodenal ulcers.

Fifteen adult men who had histories of duodenal ulcer disease were studied for 24 hours during treatment with varying intravenous doses of ranitidine (50 mg every 8 hours, 100 mg every 12 hours, 6.25 mg/hr continuous infusion, and 10 mg/hr continuous infusion) and placebo. Gastric pH was monitored under fasting conditions by means of an indwelling pH sensitive electrode. The continuous infusion regimens provided the most constant level of acid suppression. A "breakthrough" decrease in gastric pH began at approximately 6 PM at the 6.25 mg/hr dose level. The drop in pH at the 10 mg/hr dose level was less impressive. Ranitidine, 100 mg every 12 hours, resulted in better acid suppression than the regimen of 50 mg every 8 hours. A gastric pH greater than or equal to 4 was achieved 35 to 50 minutes after the start of administration for all regimens. The median effective concentration (EC50) of ranitidine was approximately 45 ng/ml. Continuous infusion regimens, with a dosage adjustment for the time of day, may be the optimal dosage regimen for patients requiring continuous protection from gastric damage by hydrochloric acid. Bolus loading doses are not required to speed the onset of effect in the clinical setting.

Adult↗
PubMed1988

Intragastric pH measurement using a novel disposable sensor.

An unique disposable pH sensor molded into the end of a nasogastric tube was tested in twelve healthy human volunteers. A Spearman's rank correlation coefficient (rs) of 0.90 was observed for the sensor and an indwelling miniature glass membrane electrode. The sensor did not correlate as well with aspirated stomach fluid (rs = 0.68). No sensor calibration was necessary and the sensors measured +/- 0.1 pH in laboratory pH buffers before and after the clinical study. Both bare and shielded disposable sensors closely agreed with a shielded miniature glass electrode.

Adult↗
PubMed1986

Relative bioavailability of two spray formulations of nitroglycerin.

Twelve healthy male volunteers received two sublingual doses of 0.4-mg nitroglycerin from two metered-dose spray products, A and B. Plasma samples were collected immediately before and for up to 6 h following each dose. The samples were immediately extracted and analyzed for nitroglycerin. The results show striking differences between the two formulations. The mean AUC for preparation A, 159 +/- 66 h X pg/mL, was 2.7 times greater than for B, 59 +/- 33 h X pg/mL. The mean maximum plasma concentration for A was 1387 +/- 620 pg/mL which was 4.1 times greater than the mean maximum plasma concentration for preparation B (340 +/- 234 pg/mL). The time of maximum plasma concentration also occurred earlier for preparation A versus B, 4.3 +/- 1.6 versus 8.3 +/- 2.0 min, respectively. Such bioavailability differences may indicate therapeutic advantages for preparation A.

Aerosols↗
PubMed1986

Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing.

Twenty-four healthy volunteers participated in a study on the disposition of ergotamine following oral and rectal administration. Plasma samples were collected surrounding each dose of medication and a new mass spectrometry method was used for quantitation of the samples. A mean peak plasma concentration of 454 pg/ml was measured an average of 50 min following a 2 mg rectal dose. In contrast, the 2 mg oral dose produced a mean peak plasma concentration of 21 pg/ml an average of 69 min following the dose. Area under the concentration time curve indicated a relative bioavailability of 5% for the oral dosage form. Conflicting data on ergotamine disposition highlight the factors which may be responsible for determining bioavailability and pharmacologic activities of the compound.

Administration, Oral↗
PubMed1986

A pharmacokinetic evaluation of celiprolol in healthy elderly volunteers.

Celiprolol is a new cardioselective beta-adrenergic blocking agent. A pharmacokinetic study in young healthy volunteers showed a nonlinear increase in AUC with increasing dose. As celiprolol will be used in elderly patients, it is necessary to establish the pharmacokinetic profile in this population. This study was established to address this question. The study was of three 7-day periods of medication with 14 days' washout between them. The first two periods were a randomized two-way crossover of celiprolol 200 mg and 400 mg, and in the third period all subjects received celiprolol 600 mg. Blood was taken for celiprolol plasma assays, to establish a 24-h profile on days 1 and 7, with trough levels in between. Subjects had a mean (+SD) age of 65.5 +/- 3.6 years (range 60-71). Model independent kinetics were used, as the data did not fit a conventional model. The AUC values (ng X h/ml) were 3,688, 9,092, and 15,020 for the celiprolol doses 200 mg, 400 mg, and 600 mg respectively on day 1, and 3,317, 9,729, and 16,550 respectively on day 7. This shows a nonlinear increase with increasing dose. A steady state was rapidly achieved, as shown by the trough levels. The Cmax for each celiprolol dose was unchanged from day 1 to day 7. The tmax was equivalent for all doses and unchanged from day 1 to day 7. The t1/2 increased slightly from 5 h on day 1 to 7 h on day 7.

Adrenergic beta-Antagonists↗
PubMed1986

The relationship between dapsone dose, serum concentration and disease severity in dermatitis herpetiformis.

20 patients with dermatitis herpetiformis maintained on once daily dosing of dapsone were studied to investigate the pharmacodynamics of dapsone in suppressing clinical disease. Multiple correlation analysis was performed on variables including dosage requirements, serum concentration of dapsone and monoacetyl dapsone, acetylation ratio, IgA-containing circulating immune complexes, adherence to a gluten-free diet, and clinical disease severity. It was found that: 1. dapsone exhibits good bioavailability in dermatitis herpetiformis with absorption being unaffected by presumed gluten-sensitive enteropathy; 2. there is wide variation in serum concentrations of dapsone and monoacetyl dapsone with no specific "therapeutic level"; 3. acetylator phenotype was unrelated to dapsone dose requirement; 4. serum dapsone concentration had only a weak correlation with disease severity; and 5. there was poor correlation between IgA circulating immune complexes and dapsone serum concentration. The use of daily dapsone dose requirements or dapsone serum concentration necessary for disease suppression as an indicator of disease severity in the research setting is inappropriate. Measurements of serum concentration of the parent drug (dapsone) or principal metabolite (monoacetyl dapsone) do not serve as a useful guide to therapeutic management.

Acetylation↗
PubMed1984

Toxicity of heparin in isolated rat hepatocytes.

The effect of heparin on isolated rat hepatocytes in monolayer culture was assessed to investigate the observed increase in serum aminotransferase activity in patients treated with heparin for thromboembolic disorders. Cells were treated with porcine intestinal mucosal heparin or beef lung heparin in concentrations ranging from 0.01 to 100 units/ml. Toxicity was evaluated based on cell damage or death measured by LDH release into the culture media as a fraction of total system LDH (LDH index). Toxicity appeared at concentrations between 1 and 10 units/ml (P less than 0.05). The uptake and binding of heparin by the hepatocyte were evaluated by addition of tritium-labeled heparin to the cultures. Sucrose gradient centrifugation with isolation of the liver plasma membranes (LPM) showed little membrane binding of heparin. The majority of intracellular heparin was located in the cytosol fraction. Heparin gains access to hepatocytes and causes a dose-related toxic effect resulting in cell damage and death. This investigation indicates that the increased serum aminotransferase concentrations seen with heparin treatment may be due to a direct hepatotoxic effect of heparin.

Animals↗
PubMed1984

Transaminase elevations in patients receiving bovine or porcine heparin.

Eighty-six patients who required heparin therapy were randomly assigned to receive bovine or porcine heparin. Abnormal concentrations of alanine transaminase and aspartate transaminase developed during treatment in 59.3% and 26.7% of patients, respectively. Patient characteristics that significantly influenced the development of abnormal alanine transaminase concentrations were male sex and higher baseline enzyme values. Transaminase concentrations returned to normal in 80% of patients after heparin therapy was discontinued and in 20% during therapy. Analysis of transaminase concentrations in all 86 patients showed that 95% had some increase in enzymes during treatment. Mean maximal increase over baseline for all patients was 3.6 for alanine transaminase and 3.1 for aspartate transaminase (range, 1.0 to 15). Lactate dehydrogenase concentrations became abnormal in 35.7% of patients. Lactate dehydrogenase isoenzyme determinations in 6 patients showed elevated hepatic fractions. No clinical symptoms of hepatic dysfunction were seen.

Adolescent↗
PubMed1979

Patterns of cell division, DNA base compositions, and fine structures of some radiation-resistant vegetative bacteria found in food.

Representative highly radiation-resistant Moraxella-Acinetobacter (M-A), Pseudomonas radiora, Micrococcus radiodurans, and Micrococcus radiophilus exhibited a wide variety of division systems and cell wall characteristics. However, the most resistant M-A possessed unusually thick cell walls, indicating a possible role of the cell wall in radiation resistance in the M-A. Thick septation was present in most of the bacteria studied, but was absent in P. radiora, thus excluding this as a necessity for high resistance. Reliable determination of the number of division planes of the M-A for use as a taxonomic criterion was achieved by the direct observation of dividing cells. The highly resistant M-A were found to divide in multiple planes and had base compositions of 54.0 to 57.5%, unlike typical Moraxella and/or Acinetobacter species. The taxonomic position of most highly resistant bacteria remains unclear.

Bacteria↗
PubMed1979

Isolation of radiation-resistant bacteria without exposure to irradiation.

Resistance to desiccation was utilized in the selection of highly radiation-resistant asporogenous bacteria from non-irradiated sources. A bacterial suspension in phosphate buffer was dried in a thin film at 25 degrees C and 33% relative humidity. Storage under these conditions for 15 days or more reduced the number of radiation-sensitive bacteria. Further selection for radiation-resistant bacteria was obtained by irradiation of bacteria on velveteen in the replication process, thereby avoiding the toxic effect of irradiated media. The similarity of radiation resistance and identifying characteristics in irradiated and non-irradiated isolates should allay some concerns that highly radiation-resistant bacteria have been permanently altered by radiation selection.

Acinetobacter↗
PubMedDate not supplied

Disposition of intravenous pirmenol.

Twelve patients having frequent premature ventricular complexes (PVCs) averaging more than 60 per hour received a single 150-mg intravenous dose of pirmenol. Plasma pirmenol concentration declined biexponentially following the infusion and was analyzed according to a two-compartment open model. Following an erratic distribution phase, the terminal elimination half-life ranged from 4.2 to 16.9 hours, with a geometric mean of 7.6 hours. Total body clearance averaged 164 +/- 58 ml/min, and the mean volume of distribution was 1.45 +/- 0.38 liter/kg. Renal clearance averaged 46.6 +/- 21.2 ml/min, representing 30 +/- 10 per cent of total body clearance. Excretion of unchanged drug in the urine averaged 31.8 +/- 8 per cent of the dose. Renal clearance and elimination half-life were correlated (r = -0.61, P less than 0.05). Eight of the 12 patients achieved greater than 95 per cent suppression of PVCs with a duration between 20 minutes and 23 hours. These favorable pharmacokinetics indicate that pirmenol may be a useful addition to the therapy of ventricular arrhythmias.

Adult↗
PubMedDate not supplied

Pathogenesis and treatment of acid peptic disorders: comparison of proton pump inhibitors with other antiulcer agents.

Acid peptic disorders, including gastric ulcers, duodenal ulcers, and gastroesophageal reflux disease, are commonly occurring conditions with high direct and indirect costs. The pathogenesis of these disorders involves an imbalance between acid secretion and gastric mucosal defenses. Pharmacologic treatment of acid peptic disorders has focused on correcting this imbalance by either improving mucosal defenses with drugs such as sucralfate, bismuth, and prostaglandin analogs, neutralizing acid with antacids, or decreasing acid secretion with histamine2 (H2)-receptor antagonists, or, more recently, proton pump inhibitors. Proton pump inhibitors are more potent inhibitors of acid secretion than H2-receptor antagonists. In clinical comparisons, proton pump inhibitors were shown to be more effective in the treatment of acid peptic disorders than H2-receptor antagonists. Helicobacter pylori infection is a factor in 85% to 100% of duodenal ulcers and 70% to 90% of gastric ulcers; eradicating this organism results in a considerable decrease in the recurrence of ulcers. Current management of peptic ulcer disease includes the use of combination antisecretory and antibiotic therapy for acute treatment of H pylori-associated disease. Patient self-medication with over-the-counter products, including H2-receptor antagonists, may have an impact on the potential for reducing the recurrence of peptic ulcer disease in patients with H pylori infection. Patients with recurrent disease should be informed of the need to seek medical treatment through aggressive education at the point of sale for over-the-counter drugs.

Anti-Ulcer Agents↗