The problem of model indistinguishability in pharmacokinetics

The problem of model indistinguishability is introduced in the context of linear compartmental models in pharmacokinetics. The two most widely used methods of analyzing model indistinguishability are described. It is shown that as the number of compartments increases, one approach, based on the Laplace transforms of the observations, although conceptually simple, can result in very large numbers of candidate models to be examined for indistinguishability, while the other approach, based on similarity transformations, although systematic, often results in very difficult algebraic expressions. These problems can be eased by the use of some simple geometrical rules, used at the outset of an indistinguishability analysis. The approach is illustrated by application of two 2-compartment drug, 2-compartment metabolite models.     

The effects of cage design on airborne allergens and endotoxin in animal rooms: high-volume measurements with an ion-charging device.

Respiratory symptoms related to both endotoxins and animal allergens continue to be an important cause of occupational disease for animal technicians and scientists working with rodents. Better sampling methods for airborne allergens and endotoxin are needed to help standardize compliance with federal occupational health regulations. Using an ion-charging device, we sampled 20 mouse rooms and four rat rooms at the University of Virginia, along with 43 domestic living rooms in houses in the Charlottesville area with at least one cat or dog. The use of filter tops on cages corresponds to a 50-fold reduction in mean levels of both airborne allergens (P < 0.001) and endotoxin (P < 0.001). The use of vented cages with filtered exhaust ports was associated with additional reductions. However, the mean airborne endotoxin level in all rooms using filter tops without a filtered exhaust port on the cages was significantly lower (P = 0.003) than the level in domestic living rooms. Our results for maximum airborne allergens or endotoxin are comparable with previous reports. However, the sensitivity of the technique allows an accurate assessment of low-level exposure, which makes it possible to evaluate the effect of cage designs. In addition, this approach allows direct comparison with results for airborne allergen and endotoxin in domestic homes. The results could allow a more consistent approach to the application of occupational health guidelines.     

Effects of a potassium channel opener (SDZ PCO 400) on guinea-pig and human pulmonary airways.

1. SDZ PCO 400 evoked dose-related relaxation of isolated airway smooth muscle. For human bronchus precontracted by endogenous tone or addition of carbachol (10(-5) M), IC50 values were 1.74 microM and 1.82 microM respectively. With guinea-pig trachea contracted by endogenous tone, a comparable IC50 (1.79 microM) was observed, but no IC50 (less than 100 microM) could be determined following contraction by carbachol (10(-6) M). 2. Airway obstruction induced by intravenous bombesin in the anaesthetized ventilated guinea-pig was diminished by intravenous injection of SDZ PCO 400 (ID50 54 micrograms kg-1) or by introduction into the duodenum (ID50 1.0 mg kg-1). Inhalation of nebulized SDZ PCO 400 (0.1 mg kg-1) diminished airway obstruction due to intravenous injection of histamine (3.2-5.6 micrograms kg-1) for up to 20 min. 3. Increased bronchoconstrictor responses to bombesin (180-240 ng kg-1) following intravenous infusion of platelet activating factor (PAF) or (+/-)-isoprenaline, or to histamine (1.0-3.2 micrograms kg-1) following intravenous injections of immune complexes, were suppressed following concomitant intravenous infusion of SDZ PCO 400 (ID50 0.3 mg kg-1 h-1, 1.0 mg kg-1 h-1 and 0.1 mg kg-1 h-1 respectively). 4. Intravenous injection of SDZ PCO 400 (0.1 mg kg-1) effected transient (less than 10 min) inhibition of histamine-induced bronchospasm, yet diminished, for prolonged periods [up to 40 min] the enhanced bronchoconstrictor responses to histamine that followed intravenous injections of immune complexes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prescribing in pregnancy. Bacterial infections in pregnancy

Certain infections, such as UTI, may have an increased incidence during pregnancy owing to physiological changes. Between 2 and 10% of pregnant women have covert or asymptomatic bacteriuria which is associated with an increased incidence of acute symptomatic UTI in later pregnancy if left untreated. Thus antenatal screening to detect the presence of bacteriuria is justified. Most women will remain abacteriuric throughout the remainder of pregnancy after a single course of antibiotic therapy but a small percentage will fail to respond or have recurrent UTIs. Maternal infection with certain organisms, namely those which resist phagocytosis, may result in transplacental infection of the fetus in utero. Congenital syphilis is preventable and antenatal serological screening is usually routinely performed. Listeriosis following maternal infection in pregnancy is less predictable and the epidemiology of L. monocytogenes remains unclear. Genital tract carriage of sexually transmitted organisms, such as N. gonorrhoeae or C. trachomatis, may also be detected during pregnancy and antibiotic therapy will be indicated to eradicate such organisms and prevent maternal and neonatal morbidity. Antibiotic therapy during pregnancy will not, however, eradicate carriage of GBS from the genital tract, although carriage status at term can now be reliably predicted by using enriched culture techniques and swabbing multiple sites on more than one occasion. Where carriage is confirmed, the administration of intrapartum antibiotics to the mother appears a useful approach in the prevention of early onset neonatal GBS disease. Broad spectrum intrapartum antibiotics may also be indicated when there are complications, such as prolonged labour or premature rupture of membranes, which are associated with a higher incidence of maternal postpartum endometritis and morbidity than in women following uncomplicated vaginal delivery. Serious postnatal sepsis and shock is fortunately now rare. The pharmacokinetics of antibiotics in late pregnancy and the puerperium are altered and maternal serum levels may be reduced by 10-50%. Most antibiotics cross the placenta and are excreted in breast milk. Some agents, such as the beta-lactams, are considered safe in pregnancy and breast-feeding women while other antibiotics are contraindicated owing to risk of toxicity (often rare) or teratogenicity (often theoretical). Caution is necessary with many agents which may cause side effects or toxicity although this does not necessarily contraindicate their use in pregnancy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Radical resection improves survival for patients with pT2 gallbladder carcinoma.

Radical resection (wedge resection of the gallbladder bed and dissection of the hepatoduodenal ligament, portal, and celiac lymph nodes) has been reported to improve survival from pathologic T2 gallbladder carcinoma (pT2 GBCa; invasion through the muscularis without perforation of the serosa). We report our experience and the outcome of patients with pT2 GBCa. Between 1989 and 2000 at Vanderbilt University Medical Center ten patients were found to have pT2 disease after cholecystectomy. The patients had an average age of 64+/-13 years and underwent either radical resection (n = 5) or no further surgical therapy (n = 5). Of the patients who underwent cholecystectomy only, one (20%) is still alive at 27 months and four (80%) died of recurrent GBCa between 6.5 and 21 months. For the patients who underwent radical resection all five are alive at 15 to 83 months with no recurrence. The proportion of patients surviving pT2 GBCa after radical resection was significantly greater than with cholecystectomy alone (P < 0.05). The difference in length of survival between the two groups was also significant (P < 0.05). Morbidity after radical resection was low (pancreatic leak in one patient), and there were no operative mortalities. Radical resection significantly improved survival over cholecystectomy alone for patients with pT2 GBCa. The procedure has low morbidity and mortality rates. Therefore a radical resection operation is indicated for patients with pT2 GBCa.     

Gastrointestinal motility and prokinetics in the critically ill

PURPOSE OF REVIEW: Enteral nutrition is frequently unsuccessful in the critically ill due to gastrointestinal dysfunction. Current treatment strategies are often disappointing. In this article upper gastrointestinal function in health together with abnormalities seen during critical illness are reviewed, and potential therapeutic options summarized. RECENT FINDINGS: Reflux oesophagitis occurs frequently due to reduced or absent lower oesophageal sphincter tone. In the stomach a number of motor patterns contribute to slow gastric emptying. The fundus has reduced compliance, there are less frequent contractions in both the proximal and distal stomach, isolated pyloric activity is increased and the organization of duodenal motor activity is abnormal. In response to nutrients, enterogastric feedback is enhanced, fundic relaxation and subsequent recovery is delayed, antral motility is further reduced and localized pyloric contractions stimulated. Elevated concentrations of hormones such as cholecystokinin and peptide YY are potential mediators for these phenomena. Rapid tachyphylaxis occurs with the commonly used prokinetics, metoclopramide and erythromycin, and novel agents are under investigation. Independent of gastric emptying, nutrient absorption is reduced. SUMMARY: There has been considerable progress in understanding the pathogenesis of mechanisms causing feed intolerance in critical illness, but this is yet to be translated into therapeutic benefit.     

The relationship between gastric emptying,plasma cholecystokinin,and peptide YY in critically ill patients

Background  

Cholecystokinin (CCK) and peptide YY (PYY) are released in response to intestinal nutrients and play an important physiological role in regulation of gastric emptying (GE). Plasma CCK and PYY concentrations are elevated in critically ill patients, particularly in those with a history of feed intolerance. This study aimed to evaluate the relationship between CCK and PYY concentrations and GE in critical illness.     

Development of verbal selective learning

Using incentive-based auditory word recall we studied the efficiency of selective learning in children ages 6-18 years. We found effects of age for both selective learning efficiency and for total words recalled, which differed in developmental trajectory. The number of words recalled showed a nonlinear component, reflecting a negatively accelerated increase with age. In contrast, the measure of selective learning was linear with age. Overall, selective learning efficiency was not related to the total number of words recalled. The findings provide a framework for interpretation of studies of selective learning in clinical populations.