Action observation for sensorimotor learning in surgery.

BACKGROUND: Acquiring new motor skills to learn complex movements and master the use of a diverse range of instruments is fundamental for developing expertise in surgery. Although aspects of skill development occur through trial and error, watching the performance of another individual (action observation) is an increasingly important adjunct for the acquisition of these complex skills before performing a procedure. The aim of this review was to examine the evidence in support of the use of action observation in surgery. METHODS: A narrative review of observational learning for surgical motor skills was undertaken. Searches of PubMed and PsycINFO databases were performed using the terms 'observational learning' OR 'action observation' AND 'motor learning' OR 'skill learning'. RESULTS: Factors such as the structure of physical practice, the skill level of the demonstrator and the use of feedback were all found to be important moderators of the effectiveness of observational learning. In particular, observation of both expert and novice performance, cueing attention to key features of the task, and watching the eye movements of expert surgeons were all found to enhance the effectiveness of observation. It was unclear, however, whether repeated observations were beneficial for skill learning. The evidence suggests that these methods can be employed to enhance surgical training curricula. CONCLUSION: Observational learning is an effective method for learning surgical skills. An improved understanding of observational learning may further inform the refinement and use of these methods in contemporary surgical training curricula.

Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease.

The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3 weeks post-surgery. Importantly, we report that cystamine has neurorestorative properties 5 weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing.

Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

MyD88 deficiency results in both cognitive and motor impairments in mice.

The myeloid differentiation primary response gene 88 (MyD88) product is the most common adaptor protein implicated in Toll-like and interleukin receptor (TIR) domain signaling and thus plays an important role in the innate immune system. Despite the fact that the MyD88-dependent pathway has emerged as an important player in cell death processes described in several animal models of neurodegenerative disorders, the contribution of this pathway to specific behavioral phenotypes has been largely ignored. To understand the full implication of this pathway, we tested MyD88(-/-) mice for both motor and cognitive functions in normal conditions. MyD88(-/-) mice displayed impaired spatial and working memory as detected by the Barnes maze, the water T-maze and the passive avoidance tests. Furthermore, MyD88(-/-) mice demonstrated hypolocomotion in the open-field and wheel activity systems, as well as impairments in motor coordination and balance using the pole test and the rotarod. Our findings shed light on behavioral alterations that are associated with the deletion of the MyD88 protein in physiological conditions. These behavioral effects should be taken into consideration when assessing the role of the MyD88-dependent pathway in various infectious and non-infectious conditions.

Thin-Slice Pituitary MRI with Deep Learning-Based Reconstruction for Preoperative Prediction of Cavernous Sinus Invasion by Pituitary Adenoma: A Prospective Study.

BACKGROUND AND PURPOSE: Accurate radiologic prediction of cavernous sinus invasion by pituitary adenoma remains challenging. We aimed to assess whether 1-mm-slice-thickness MRI with deep learning-based reconstruction can better predict cavernous sinus invasion by pituitary adenoma preoperatively and to estimate the depth of invasion and degree of contact in relation to the carotid artery, compared with 3-mm-slice-thickness MRI. MATERIALS AND METHODS: This single-institution, prospective study included 67 consecutive patients (mean age, 53 [SD, 12] years; 28 women), between January and August 2020, who underwent a combined contrast-enhanced T1-weighted imaging protocol of 1-mm-slice-thickness MRI + deep learning-based reconstruction and 3-mm-slice-thickness MRI. An expert neuroradiologist who was blinded to the imaging protocol determined cavernous sinus invasion using the modified Knosp classification on 1-mm-slice-thickness MRI + deep learning-based reconstruction and 3-mm-slice-thickness MRI, respectively. Reference standards were established by the consensus of radiologic, intraoperative, pathologic, and laboratory findings. The primary end point was the diagnostic performance of each imaging protocol, and the secondary end points included depth of invasion and degree of contact in relation to the carotid artery. RESULTS: The diagnostic performance of 1-mm-slice-thickness MRI + deep learning-based reconstruction (area under the curve, 0.79; 95% CI, 0.69 - 0.89) in predicting cavernous sinus invasion by pituitary adenoma was higher than that of 3-mm-slice-thickness MRI (area under the curve, 0.61; 95% CI, 0.52-0.70; P < .001). One-millimeter-slice-thickness MRI + deep learning-based reconstruction demonstrated greater depth of invasion by pituitary adenomas from the medial intercarotid line than 3-mm-slice-thickness MRI (4.07 versus 3.12 mm, P < .001). A higher proportion of cases were in a greater degree of contact with the intracavernous ICA with 1-mm-slice-thickness MRI + deep learning-based reconstruction than with 3-mm-slice-thickness MRI (total encasement, 37.3% versus 13.4%, P < .001; >270°, 38.8% versus 16.4%, P < .001). CONCLUSIONS: Compared with 3-mm-slice-thickness MRI, 1-mm-slice-thickness MRI + deep learning-based reconstruction showed a higher diagnostic performance in preoperatively predicting cavernous sinus invasion by pituitary adenomas and demonstrated a greater depth and degree of contact in relation to the carotid artery.

Clinical Presentations and Outcomes of Children in Canada With Recurrent Invasive Pneumococcal Disease From the IMPACT Surveillance Network.

BACKGROUND: Invasive pneumococcal disease due to Streptococcus pneumoniae can cause mortality and severe morbidity due to sepsis, meningitis and pneumonia, particularly in young children and the elderly. Recurrent invasive pneumococcal disease is rare yet serious sequelae of invasive pneumococcal disease that is associated with the immunocompromised and leads to a high mortality rate. METHOD: This retrospective study reviewed recurrent invasive pneumococcal disease cases from the Canadian Immunization Monitoring Program, ACTive (IMPACT) between 1991 and 2019, an active network for surveillance of vaccine-preventable diseases and adverse events following immunization for children ages 0-16 years. Data were collected from 12 pediatric tertiary care hospitals across all 3 eras of public pneumococcal conjugate vaccine implementation in Canada. RESULTS: The survival rate within our cohort of 180 recurrent invasive pneumococcal disease cases was 98.3%. A decrease of 26.4% in recurrent invasive pneumococcal disease due to vaccine serotypes was observed with pneumococcal vaccine introduction. There was also a 69.0% increase in the rate of vaccination in children with preexisting medical conditions compared with their healthy peers. CONCLUSION: The decrease in recurrent invasive pneumococcal disease due to vaccine-covered serotypes has been offset by an increase of non-vaccine serotypes in this sample of Canadian children.

Specific protein-protein interaction between basic helix-loop-helix transcription factors and homeoproteins of the Pitx family.

Homeoproteins and basic helix-loop-helix (bHLH) transcription factors are known for their critical role in development and cellular differentiation. The pituitary pro-opiomelanocortin (POMC) gene is a target for factors of both families. Indeed, pituitary-specific transcription of POMC depends on the action of the homeodomain-containing transcription factor Pitx1 and of bHLH heterodimers containing NeuroD1. We now show lineage-restricted expression of NeuroD1 in pituitary corticotroph cells and a direct physical interaction between bHLH heterodimers and Pitx1 that results in transcriptional synergism. The interaction between the bHLH and homeodomains is restricted to ubiquitous (class A) bHLH and to the Pitx subfamily. Since bHLH heterodimers interact with Pitx factors through their ubiquitous moiety, this mechanism may be implicated in other developmental processes involving bHLH factors, such as neurogenesis and myogenesis.

Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase.

Werner syndrome is an autosomal recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases, including malignancy. To assess a potential collaboration between p21 or p53 cell cycle regulators and Wrn proteins, Wrn mutant mice were created and mated with p21 or p53 null mice to generate double mutants. The p21 null/Wrn mutant mice did not show an acceleration of tumorigenesis during the first year of life, suggesting that the p53-dependent G1-S cell cycle checkpoint (which operates via p21) is not involved in Wrn-abetted tumor suppression. In contrast, the p53 null/Wrn mutant mice were particularly remarkable with respect to the rapidity with which they developed tumors. These mice were also distinguished by the variety of tumors they developed compared to those that developed in p53 null mice. Such data suggest a genetic interaction between p53 and Wrn in which loss of Wrn provokes a more variable p53 response unrelated to its role in the G1-S cell cycle checkpoint.

Decreased Fas antigen receptor expression in testicular tumor cell lines derived from polyomavirus large T-antigen transgenic mice.

MT-PVLT-10 transgenic mice express large T-antigen of polyomavirus under the control of the mouse metallothionein-1 promoter and mates of this transgenic line develop testicular tumors at advanced ages. The differential display technique was employed to compare mRNA expression from immortalized cell lines derived from normal or adenomatous testis from MT-PVLT-10 transgenic males. Using this technique, a complementary DNA fragment corresponding to the mouse Fas antigen receptor was recovered from normal testicular cells but not from tumor cells. RNAse protection assays with the Fas antigen specific fragment confirmed its differential expression. Normal testicular cells from the transgenic animals responded to treatment of interferon-gamma by increasing the expression of Fas antigen specific mRNA and were sensitive to the proliferative inhibitory effect of anti-Fas antibody in vitro. This proliferative inhibition was characterized by an accumulation of cells in S phase of the cell cycle. In contrast, the testicular tumor cells did not respond to either interferon-gamma or to anti-Fas antibody in vitro. These results suggest that the toss of proliferative inhibitory effect mediated by the Fas antigen pathway in tumor cells may be an important step in testicular tumor progression in the MT-PVLT-10 transgenic mice.

The Ask-Upmark kidney: a curable cause of hypertension in young patients.

We are reporting a case of arterial hypertension in a young woman who had an atrophic kidney with a cortical groove and histological features of the Ask-Upmark kidney. Her hypertension was renin dependent and the patient was cured following nephrectomy. Controversy on the pathogenesis of this clinical entity is briefly reviewed.

[New trends in pediatric endocarditis]. / Nuevas tendencias de la endocarditis pediátrica.

OBJECTIVES: To evaluate the epidemiology, etiology and outcome of endocarditis in a cohort of pediatric patients and to compare the main characteristics with our previous experience. MATERIAL AND METHODS: Patients aged less than 18 years of age diagnosed with endocarditis at the Sainte-Justine Hospital, University of Montreal between 1-1986 and 12-2000 were studied. The recent case series was compared with our previous experience from 1960-1985. RESULTS: Fifty-six children with endocarditis were included in the 1986-2000 series: 35 children with congenital heart disease, 15 with serious underlying disease and six healthy children. The mean age was 7 years and 10 months. Fifty-four percent of the patients were boys. The incidence of endocarditis increased from 1.5 cases/year in the 1986-2000 series to 4 cases/year in the 1986-2000 series. In the 1986-2000 series, 10 (17.9 %) patients had a central catheter. Sixteen (28.6 %) patients had a vascular prosthesis. Blood cultures were positive in 50 patients (89 %): Streptococci were found in 48 % of the patients and Staphylococci in 34 %. Echocardiography was positive in 36 of 55 patients (65.4 %). All children were treated with intravenous antibiotics for a mean of 43 +/- 15 days. There were no recurrences. Significant morbidity developed in 26 patients (46 %). Embolic phenomena were seen in 11 children (20 %). Twelve patients (21 %) needed surgery. Of the six healthy children, five developed complications. Overall, seven children (12.5 %) died; all were older than 6 years of age. Comparing our experience from 1960-1985 with that from 1986-2000 revealed that morbidity decreased from 85.7 % to 46.4 % and mortality decreased from 27 % to 12.5 %. CONCLUSIONS: Physicians must recognize that children with underlying immunodeficiency and those with central catheters have an increased risk of endocarditis. Healthy children with endocarditis have a greater risk of complications. Morbidity and mortality due to endocarditis has diminished considerably in recent years.

Endocrine sodium and volume regulation in familial hyperkalemia with hypertension.

The hormonal regulation of sodium and volume homeostasis was investigated in three patients (two related) with the syndrome of familial hyperkalemic acidosis and hypertension with normal glomerular filtration rate. Recumbent plasma renin activity was low during normal sodium intake (135 mmol daily), and the response to upright posture or to low sodium diet (10 mmol daily) was blunted. Recumbent plasma aldosterone levels were normal in two patients and high in one, and the standing values were elevated in one; responses to upright posture were brisk on low sodium diet. Angiotensin II infusion induced a marked increase in plasma aldosterone. Plasma atrial natriuretic peptide was at the upper limit of normal during normal sodium intake, decreased during diuretic therapy, and increased during sodium chloride infusion in one patient. Basal urinary prostaglandin E2, prostaglandin F2 alpha, and 6-ketoprostaglandin F1 alpha excretion rates were decreased, and thromboxane B2 was increased. Total blood and plasma volumes were subnormal, whereas extracellular fluid volume and exchangeable sodium values were close to or above (in one patient) the mean normal values. Chronic treatment with hydrochlorothiazide in two patients corrected the hyperkalemic acidosis and hypertension, but on its discontinuation (in one patient) all biochemical abnormalities promptly reappeared.

Prostanoids and aldosterone-induced mild experimental hypertension in rats.

The goal of this study was to determine the role of prostanoids in a new model of mineralocorticoid-dependent hypertension induced by the subcutaneous infusion of aldosterone (1 micrograms/hr) to normal male Sprague-Dawley rats. This regimen caused a mild and gradual increase in systolic pressure over a period of 4 weeks (113 +/- 1 vs. 137 +/- 3 mm Hg) and was associated with an increase in the in vivo formation of prostaglandins I2 and E2 and of thromboxane A2 in the kidney. High sodium intake induced a fall in the urinary levels of prostaglandin E2 and a rise in the arterial pressure of control rats (126 +/- 1 vs. 113 +/- 1 mm Hg) but did not influence aldosterone-induced hypertension. Indomethacin (3.0 mg/kg/day) caused a profound inhibition of the in vivo synthesis of prostaglandin I2 and thromboxane A2 without modifying the renal production of prostaglandin E2. Although indomethacin exerted no effect on aldosterone-induced hypertension in rats fed a normal diet, it caused a further rise in systolic pressure in aldosterone-treated rats fed a high sodium diet (157 +/- 6 vs. 140 +/- 4 mm Hg). The results of this study in a model of aldosterone-induced mild hypertension in the rat indicate that 1) aldosterone exerts a stimulatory effect on the renal synthesis of prostanoid, particularly prostaglandin E2; 2) thromboxane A2 and prostaglandin I2 do not seem to play a role in aldosterone-induced hypertension under conditions of normal dietary salt intake, whereas the role of prostaglandin E2 is unclear; 3) there is enough sodium in a normal diet to allow for the maximal expression of the hypertensive effect of aldosterone; 4) prostaglandin I2 seems to play a significant role in modulating the cardiovascular impact of a high sodium diet in aldosterone-treated rats; and 5) the renal biosynthesis of prostaglandin E2 is particularly resistant to the inhibitory effect of indomethacin in vivo.

Influence of the menstrual cycle on the absorption and elimination of D-xylose.

Thirteen healthy female volunteers with regular menstrual cycles (28 +/- 2 days) received 25 gm oral and 5 gm intravenous doses of D-xylose on 2 successive days during the follicular, ovulatory, and luteal phases of two consecutive menstrual cycles. The ovulation time was characterized by luteinizing hormone levels, body basal temperatures, and progesterone and estradiol serum levels. D-Xylose was assayed in plasma and urine with a phloroglucinol-based colorimetric method. The findings of this study indicated that menstrual cycle did not significantly affect D-xylose absorption. After oral administration, the total clearance was significantly increased in cycle 2 during the luteal phase (p = 0.004). After intravenous administration in both cycles, D-xylose total clearance was also significantly faster during the luteal phase (p = 0.038 and p = 0.041, respectively). After oral administration, the renal clearance tended to be higher during the luteal phase in both cycles studied. After intravenous administration, this parameter was increased during the luteal phase by 24% and 25% in cycle 1 and by 8% and 12% in cycle 2. These findings are consistent with those of others showing an increase in glomerular filtration rate (GFR) during the luteal phase of the menstrual cycle. The findings of this study seem to be explained by the hormonal changes occurring during the menstrual cycle. Further investigations are warranted with use of specific probes of renal processes (GFR, renal reabsorption and tubular secretion) to confirm our findings and to elucidate the underlying mechanisms.

Labetalol infusion in hypertensive emergencies.

The antihypertensive effects of labetalol infusion (2 mg/min; maximal dose 150 mg) were evaluated in 22 subjects requiring rapid lowering of blood pressure because of severe hypertension, a hypertensive crisis after surgery, or before angiographic examination. Overall systolic and diastolic blood pressures were reduced from 201 +/- 4 to 164 +/- 4 mm Hg and from 123 +/- 3 to 107 +/- 3 mm Hg, respectively. By the end of the infusion, diastolic blood pressure in 16 (73%) subjects was lowered to less than or equal to 110 mm Hg. No adverse effects were encountered, but one subject had a transitory hypotensive episode that did not require treatment. Intravenous labetalol appears effective and well tolerated in the control of blood pressure in hypertensive emergencies.

Intravenous ciprofloxacin disposition in obesity.

The pharmacokinetics of ciprofloxacin and its metabolite 1 (desethyleneciprofloxacin) were studied in 17 obese men (mean age, 29.2 +/- 7.5 years; mean weight, 110.7 +/- 20.2 kg; mean body mass index, 36.4 +/- 3.9 kg/m2) and 11 control subjects (men of normal weight; mean age, 25.0 +/- 5.1 years; mean weight, 71.8 +/- 9.9 kg; mean body mass index, 23.3 +/- 2.4 kg/m2). Each subject received a single 400 mg intravenous dose of ciprofloxacin infused over 1 hour. Ciprofloxacin total clearance was significantly increased in obese subjects compared with control subjects (897.44 +/- 159.57 versus 744.44 +/- 120.51 ml/min, respectively; p < 0.05). Ciprofloxacin renal clearance in obese subjects (637.58 +/- 128.89 ml/min) was 29% higher than in control subjects (495.47 +/- 137.85 ml/min; p < 0.05). The elimination half-life values of ciprofloxacin and desethyleneciprofloxacin were not statistically different between groups. Ciprofloxacin steady-state volume of distribution (Vss) was significantly larger in obese group (269.17 +/- 51.64 versus 219.03 +/- 35.80 L; p < 0.01) compared with the control group, and when it was normalized by total body weight, obese subjects exhibited lower Vss/kg than control subjects (2.46 +/- 0.42 versus 3.06 +/- 0.31 L/kg; p < 0.001). These findings indicate that ciprofloxacin is distributed less to adipose tissue than to other tissues, but partial distribution to adipose tissue does occur. To normalize the volume of distribution of obese subjects to that of normal weight subjects, 45% of excess weight (total body weight minus ideal body weight) must be added to the ideal body weights of obese subjects.

The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. CONCLUSION: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.

Caffeine metabolism in cystic fibrosis: enhanced xanthine oxidase activity.

STUDY OBJECTIVE: To characterize the activities of the P450 mixed-function oxidase CYP1A2 as well as the cytosolic enzymes N-acetyltransferase and xanthine oxidase using caffeine as a probe in children with cystic fibrosis compared to age-matched healthy control subjects. METHODS: After administration of caffeine (cola beverage) to 12 children with cystic fibrosis (age range, 5 to 11 years) and 12 healthy control subjects (age range, 5 to 12 years), urine was collected for 4 hours. Caffeine metabolites were determined by HPLC, and urinary caffeine metabolite ratios were computed to determine liver enzyme activities. In addition, a blood sample was used to detect cystic fibrosis mutant alleles by polymerase chain reaction. RESULTS: The indexes for CYP1A2, N-acetyltransferase, and 8-hydroxylation were similar in both groups of subjects. In contrast, there was a significant difference in the frequency distribution of the xanthine oxidase activity between the two groups. Nine of 12 patients with cystic fibrosis but only one of 12 healthy volunteers had xanthine oxidase activities above 0.42 (Kolmogorov-Smirnov two-sample test, p < 0.01). CONCLUSIONS: Differences in xanthine oxidase may have clinical implications with regard to interindividual variation in xenobiotic biotransformation and the exposure to lung tissue-damaging oxygen radicals. Hepatic enzyme activities appear to be selectively altered in patients with cystic fibrosis.

Altered disposition of fleroxacin in patients with cystic fibrosis.

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.

A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine.

BACKGROUND AND OBJECTIVES: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use. METHODS: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state. Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method. RESULTS: A total of 28 subjects completed the study. Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%. CONCLUSION: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.