Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

Nonfatal childhood injuries: a survey at the Children's Hospital of eastern Ontario.

OBJECTIVE: To examine the types and severity of injuries seen in the Emergency Department of the Children's Hospital of Eastern Ontario and the circumstances surrounding the events. DESIGN: Chart review. SETTING: A tertiary care hospital that serves a child population of 600,000 in eastern Ontario and western Quebec. PARTICIPANTS: Every sixth day's charts of children up to 17 years of age who visited the Emergency Department because of injuries between Sept. 1, 1984, and Aug. 31, 1985, were examined retrospectively. RESULTS: A total of 2886 charts were reviewed. There were more boys than girls. Most (1354 [46.9%]) of the accidents had occurred at home. Falls and sports-related accidents were the leading causes of injury (in 1088 [37.7%] and 560 [19.4%] of the cases respectively). Most of the visits were for minor injuries (bumps, swellings, cuts, bruises and scrapes), and only 114 (4.0%) of the children were admitted to the hospital. Injuries from motor vehicle accidents accounted for the highest admission rate (17.4%). Important information regarding the circumstances surrounding the events (e.g., whether a seat belt or car seat was used) was frequently missing from the charts. CONCLUSIONS: Nonfatal injuries are common, especially in or around the home, and remain a significant problem in our society in terms of radiographic and consulting fees, time off from school or work and pain. Given the difficulties in obtaining information on the circumstances surrounding the events prospective studies are needed. Factors related to the occurrence and severity of childhood injury and whether these factors can be altered remain a high priority for research.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

Bilateral malignant glaucoma.

Two cases of bilateral malignant glaucoma are presented. In one case the condition developed sequentially in the two eyes; pars plana vitrectomy was eventually needed in the operated eye, whereas the condition responded to medical treatment in the fellow eye. In the second case the two eyes were involved simultaneously nearly 1 year after surgery, and the glaucoma responded to medical treatment.     

An epidemiologic study of smoking and primary infertility in women.

OBJECTIVE: To determine the relationship between cigarette smoking and primary female infertility. DESIGN: Retrospective, case-control study. SETTING: Population-based and randomly selected from eight geographic areas in the United States. PARTICIPANTS: Women, 20 to 54 years of age, who were randomly selected to serve as the control group of the Cancer and Steroid Hormone Study were used for this study. Within this group, there were 483 women who were classified as having experienced primary infertility and 2,231 women eligible to serve as controls. Primary infertility, defined as 24 consecutive months of unprotected intercourse without conception, was documented from a calendar of each women's reproductive and contraceptive history. RESULTS: Smoking one pack of cigarettes per day (odds ratio = 1.36) and starting to smoke before 18 years of age (odds ratio = 1.30) were significantly associated with increased risk of infertility. Life table and proportional hazards analysis indicated that smoking did not significantly increase the time required to conceive among infertile women. CONCLUSIONS: Number of cigarettes smoked and age when the women began smoking contributed to infertility in this study. It is reasonable, therefore, to recommend that women stop smoking when they are attempting to become pregnant.     

The Breast Cancer Screening Program in Rhode Island.

The Rhode Island Department of Health has undertaken a Breast Cancer Screening Program which incorporates assessment, policy development, and assurance functions, following the model proposed in the Institute of Medicine (IOM) report, The Future of Public Health. With the community's help, projects have been implemented to increase screening capacity with dedicated, state-of-the-art equipment, to increase screening accessibility, to publicize the need for mammography, and to minimize false test results. In the program's first 15 months, the proportion of women ages 40 and over who were screened with mammography according to current guidelines increased from 35 to 46 percent (from 38 to 49 percent among women ages 40-49; from 31 to 43 percent among women ages 50 and over), including 15 percent who received their first screening mammogram. Providers' recommendations and knowledge of screening guidelines were important in explaining first-time use. The Department plans to apply the IOM model in other program areas. Its adoption by others is urged.     

Postamputation Pain and Sensory Changes in Treatment-naive Patients: Characteristics and Responses to Treatment with Tramadol, Amitriptyline, and Placebo

Background: Pain after amputation is common but difficult to treat, and few controlled treatment studies exist.

Methods: In the current study, 94 treatment-naive posttraumatic limb amputees with phantom pain (intensity: mean visual analog scale score [0-100], 40 [95% confidence interval, 38-41]) were randomly assigned to receive individually titrated doses of tramadol, placebo (double-blind comparison), or amitriptyline (open comparison) for 1 month. Nonresponders were crossed over to the alternative active treatment.

Results: After 1 month, phantom pain intensity was 1 (0-2) in the 48 tramadol responders (mean dose, 448 mg [95% confidence interval, 391-505 mg]), 0 (0-0) in the 40 amitriptyline responders (55 [50-59] mg), and 0 (0-0) in the 2 placebo responders, with similar effects on stump pain. Cytochrome P-450 2D6 slow metabolizers derived greater analgesia from tramadol and less from amitriptyline compared with fast metabolizers in the first treatment week (P < 0.01). Electrical pain thresholds increased and pain during suprathreshold stimulation decreased markedly on the stump and, to a lesser extent, on the contralateral limb after 1 month of treatment with amitriptyline or tramadol. Adverse effects were minor in all groups, but more common with tramadol.     

Local anesthesia for inguinal hernia repair in adolescents

Background Many centers use local anesthesia for adult inguinal hernia surgery in the setting of day-case surgery. There are no reports on, or guidelines for, use of anesthesia for inguinal hernia surgery in adolescents. We describe our initial experience with the use of local anesthesia and intravenous sedation for inguinal hernia surgery in adolescents in the setting of a day-surgery facility. Methods The charts of 14 consecutive adolescent patients (aged 12–17) who had inguinal hernia surgery from July 2004 to March 2005 were reviewed retrospectively. Intravenous sedation was administered 1–3 min before injection of local anesthetic. Sedation consisted of midazolam 0.085 mg kg⁻¹ and either fentanyl 0.85 μg kg⁻¹ or ketamine 0.085 mg kg⁻¹, according to the preference of the anesthesiologist. Additional sedation with half the initial dose was administered if required. Local anesthesia using a combination of lignocaine and bupivacaine was administered by the surgeon with infiltration in the skin and deep tissues. Results Fourteen adolescents aged 12–17 years (mean 14.8 ± 1.37), weighing 34–100 kg (mean 61.2 ± 16.5), had 15 inguinal hernia repairs with sedation and local anesthesia. All the patients were male. All completed the surgery with sedation and local anesthesia. None required conversion to general anesthesia. There were no immediate or subsequent complications. Mean time from the end of surgery to discharge home was under 2 h (mean 106 ± 36 min). Examination of patient charts did not reveal any complaints regarding the surgery or the postoperative course at the postoperative follow up visit. Conclusions The use of local anesthesia with intravenous sedation for inguinal hernia repair in the adolescent age group seems feasible and requires further prospective study.