Classification analysis of P-glycoprotein substrate specificity

Prediction of P-glycoprotein substrate specificity (S(PGP)) can be viewed as a constituent part of a compound's "pharmaceutical profiling" in drug design. This task is difficult to achieve due to several factors that raised many contradictory opinions: (i) the disparity between the S(PGP) values obtained in different assays, (ii) the confusion between Pgp substrates and inhibitors, (iii) the confusion between lipophilicity and amphiphilicity of Pgp substrates, and (iv) the dilemma of describing class-specific relationships when Pgp has no binding sites of high ligand specificity. In this work, we compiled S(PGP) data for 1000 compounds. All data were represented in a binary format, assigning S(PGP) = 1 for substrates and S(PGP) = 0 for non-substrates. Each value was ranked according to the reliability of experimental assay. Two data sets were considered. Set 1 included 220 compounds with S(PGP) from polarized transport across MDR1 transfected cell monolayers. Set 2 included the entire list of 1000 compounds, with S(PGP) values of generally lower reliability. Both sets were analysed using a stepwise classification structure-activity relationship (C-SAR) method, leading to derivation of simple rules for crude estimation of S(PGP) values. The obtained rules are based on the following factors: (i) compound's size expressed through molar weight or volume, (ii) H-accepting given by the Abraham's beta (that can be crudely approximated by the sum of O and N atoms), and (iii) ionization given by the acid and base pKa values. Very roughly, S(PGP) can be estimated by the "rule of fours". Compounds with (N + O) > or = 8, MW > 400 and acid pKa > 4 are likely to be Pgp substrates, whereas compounds with (N + O) < or = 4, MW < 400 and base pKa < 8 are likely to be non-substrates. The obtained results support the view that Pgp functioning can be compared to a complex "mini-pharmacokinetic" system with fuzzy specificity. This system can be described by a probabilistic version of Abraham's solvation equation, suggesting a certain similarity between Pgp transport and chromatographic retention. The chromatographic model does not work in the case of "marginal" compounds with properties close to the "global" physicochemical cut-offs. In the latter case various class-specific rules must be considered. These can be associated with the "amphiphilicity" and "biological similarity" of compounds. The definition of class-specific effects entails construction of the knowledge base that can be very useful in ADME profiling of new drugs.     

Antibiotic prophylaxis in urologic prosthetic surgery

The implantation of prosthetic devices is an ever-increasing practice in urologic surgery. The most common devices are penile prostheses, artificial urinary sphincters, synthetic pubovaginal slings, and bone anchors used for pelvic floor reconstruction and incontinence surgery. While their efficacy has been supported over time, infection and rejection are severe complications. Explantation of the entire prosthetic device has been the standard treatment of such complications, often necessitating long-term antibiotics and prolonged recovery before future reimplantation. The dense inflammatory response associated with prosthetic surgery may obliterate tissue planes and further complicate reoperative efforts. These factors support the need for effective antibiotic prophylaxis, with the goal of preventing bacterial seeding of the prosthesis during implantation. Antibiotic regimens should be effective against biofilm-forming bacteria, especially S. epidermidis and P. aeruginosa, and vancomycin should be a mainstay. Prevention of intraoperative infection by treating existing skin and urinary tract reservoirs and employing strict sterile technique cannot be overemphasized. While data is scant, it appears that routine prophylaxis prior to dental procedures, in patients with urologic prostheses, is unwarranted; however, if the patient is immunocompromised or has severe comorbidities, prophylaxis should be employed.     

Contact lenses for the treatment of pediatric cataracts

OBJECTIVE: To evaluate the experiences, attitudes, and perceptions of the caregivers of children with cataracts who were visually rehabilitated with contact lenses. PARTICIPANTS: One hundred twenty-three caregivers of children <8.1 years old treated for unilateral and bilateral cataracts at one pediatric hospital. DESIGN: Survey by questionnaire. INTERVENTION: Primary caregivers were asked to complete an anonymous questionnaire. MAIN OUTCOME MEASURES: Caregiver responses to questions assessing background and demographic and clinical information, as well as perceptions, attitudes, levels of compliance, and anxiety with respect to treatment, were reviewed. Caregivers were also asked to choose between aphakic rehabilitation with contact lenses, aphakic glasses, or intraocular lenses, given various hypothetical scenarios differing in regard to their final visual prognosis, risks of treatment complications, and cost. RESULTS: The response rate was 82.9%. Absolute average stress levels for contact lens use were 1.36 +/- 1.79 and 0.79 +/- 1.48 (scale, 0-5) for insertion and removal, respectively, compared with 4.03 +/- 1.64 and 2.40 +/- 1.92 for cataract surgery and patching therapy, respectively. Although average paired initial resistance to treatment (RT) levels for contact lens insertion and removal on a scale of 0 to 3 were high (2.09 +/- 1.15) and moderate (1.63 +/- 1.20), respectively, final RT levels were significantly lower (1.09 +/- 1.14 and 0.66 +/- 1.07, respectively; P < 0.0001). The vast majority of caregivers chose contact lens use in hypothetical scenarios that depicted realistic expectations for other forms of aphakic rehabilitation. CONCLUSIONS: In our study, contact lenses seemed to be well tolerated by most patients, as assessed by caregivers. Although initial resistance to contact lens use is high, this decreases with time. Relative to other events in the treatment of pediatric cataracts, contact lens use is not a major stressor for most caregivers and patients. This study supports the notion that contact lenses should continue to receive serious consideration as a treatment option for pediatric cataracts.     

Bayesian analysis of quantitative antimicrobial assays

Quantitative antimicrobial assays are used to assess the efficacy of chemical germicides. Standard methods for statistical analysis use log reduction (LR), the difference on the log scale between average surviving microbes for control and test carriers, as an efficacy measure. These methods have several deficiencies. The LR parameter is not on the original response scale, which complicates its interpretation. The presence of two different definitions of LR makes the statistical inference even more difficult. Current statistical methods for antimicrobial assay analysis rely on asymptotic normal theory, which might not work well for small samples. In addition, they do not appropriately incorporate censored ('too numerous to be counted') observations in the analysis. To overcome those problems, a new Bayesian approach is introduced here. It has also the advantages of more flexible statistical inference, and incorporated prior information in the model.     

Economics of one-stage versus two-stage bilateral total knee arthroplasties

Patients requiring bilateral total knee arthroplasties may have both joints replaced simultaneously during one hospitalization (one-stage) or during two separate hospitalizations (two-stage). The goals of the current study were to retrospectively analyze discharge patterns for 91 patients who had one-stage bilateral total knee arthroplasties and 32 patients who had two-stage surgeries, and to quantify their in-hospital costs and their costs if the patients were discharged from the hospital to an inpatient unit. Patients having one-stage and two-stage surgery were similar in age, gender, severity of illness (as measured by the American Society of Anesthesiologists Physical Status score), principal diagnosis, and ethnicity. Using a microcosting approach, the authors found that the average in-hospital costs for one-stage total knee arthroplasty (27,468 US dollars) were significantly lower (by 24%) than for two-stage total knee arthroplasty. However, 38% of patients who had the one-stage bilateral total knee arthroplasties were admitted to an acute rehabilitation unit, which had a mean cost of 6469 US dollars and length of stay of 9 days. In contrast, none of the patients who had the two-stage procedure required acute rehabilitation. Patients who had the two-stage procedure were discharged directly home (or with home health services) 42% of the time, versus 21% for patients who had the one-stage procedure. Patients from both groups were discharged to a skilled nursing facility approximately (1/2) of the time, accruing similar costs. Economic analyses of the one-stage procedure need to consider that these patients will require increased use of acute inpatient rehabilitation after hospital discharge.     

Fatty metastatic lesions in 2 patients with renal clear-cell carcinoma

This is a case report of 2 patients with previously resected renal cell carcinoma who present with unusual fatty lesions that proved to be metastases.     

Neuronal overexpression of COX-2 results in dominant production of PGE2 and altered fever response

Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE(2) over other prostaglandins, followed by more modest inductions of PGI(2), and relatively smaller increases in PGF(2alpha),PGD(2), and TxB(2). We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1 2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.     

Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer

Current epidemiological evidence supports a pathogenetic model of gastric cancer involving intermediate stages that include chronic gastritis and intestinal metaplasia. This study explores the molecular features of gastric cancer and premalignant stages using DNA microarray-based gene expression profiling and relates these findings to clinical, pathological, and ethnic parameters. A total of 124 tumor and adjacent mucosa samples were analyzed using spotted cDNA microarrays containing 9381 nonredundant gene elements. Tumor specimens were diffuse, intestinal, or mixed gastric cancer and adjacent mucosa, which generally displayed signs of chronic gastritis or intestinal metaplasia. Expression patterns could be discerned that readily defined premalignant and tumor subtypes. Chronic gastritis exhibits a pronounced mitochondrial gene expression signature, which may be linked to Helicobacter pylori pathogenesis. Intestinal metaplasia was associated with increased expression of many intestinal differentiation genes, many of which were not overexpressed in tumors. Samples were obtained from 91 Australian and 33 Chinese patients to explore potential variation in gene expression between these populations. Despite differences in the incidence, and potentially the etiology, of gastric cancer between these ethnic groups, we found the tumors to be molecularly similar. The identification of molecular signatures that are characteristic of subtypes of gastric cancer and associated premalignant changes should enable further analysis of the steps involved in the initiation and progression of this disease.     

Attitudes about prescribing take-home naloxone to injection drug users for the management of heroin overdose: a survey of street-recruited injectors in the San Francisco Bay Area

Naloxone, an injectable opiate antagonist, can immediately reverse an opiate overdose and prevent overdose death. We sought to determine injection drug users’ (IDUs) attitudes about being prescribed take-home naloxone. During November 1999 to February 2000, we surveyed 82 street-recruited IDUs from the San Francisco Bay Area of California who had experienced one or more heroin overdose events. We used a questiomaire that included structured and open-ended questions. Most respondents (89%) had witnessed an overdose, and 90% reported initially attempting lay remedies in an effort to help companions survive. Only 51% reported soliciting emergency assistance (calling 911) for the last witnessed overdose, with most hesitating due to fear of police involvement. Of IDUs surveyed, 87% were strongly in favor of participating in an overdose management training program to receive take-home naloxone and training in resuscitation techniques. Nevertheless, respontdents expressed a variety of concerning attitudes. If provided naloxone, 35% predicted that they might feel comfortable using greater amounts of heroin, 62% might be less inclined to call 911 for an overdose, 30% might leave an overdose victim after naloxone resuscitation, and 46% might not be able to dissuade the victim from using heroin again to alleviate with drawal symptoms induced by naloxone. Prescribing take-home naloxone to IDUs with training in its use and in resuscitation techniques may represent a life-saving, peer-based adjunct to accessing emergency services. Nevertheless, strategies for overcoming potential risks associated with the use of take-home naloxone would need to be emphasized in an overdose management training program.