CISPLATIN NEPHROTOXICITY AND ITS EFFECTS ON GENTAMICIN PHARMACOKINETICS

Myelosuppression is a common side effect of anticancer agents such as cisplatin. This makes patients more susceptible to infections. Gentamicin is an aminoglycoside antibiotic that is very effective in the treatment of gram negative infections. Both these drugs are excreted by the kidney, and are also nephrotoxic. Thus, each may affect the disposition of the other. This project deals with the nature and duration of the effects of cisplatin on gentamicin pharmacokinetics in F-344 rats.^ The appropriate cisplatin dose was determined by comparing the nephrotoxicity of four intravenous doses--3, 4, 5, and 6 mg/kg. The 6 mg/kg dose gave the most consistent nephrotoxic effect, with peak plasma urea nitrogen and creatinine levels on the 7th day. Plasma and tissue gentamicin levels were compared between rats given gentamicin alone (30 mg/kg, intraperitoneally, twice a day for four days), and those given cisplatin (6 mg/kg, intraperitoneally) with the first gentamicin dose. Cisplatin caused a significant elevation of gentamicin levels in plasma, liver, and spleen. However, cisplatin given in three weekly doses of 2 mg/kg each, had no effect on plasma or tissue gentamicin levels.^ In order to determine the duration of cisplatin effects, a single dose of gentamicin (30 mg/kg, intravenously) was given to different groups of rats either alone, or on day 1, 4, 7, 15, or 29 following cisplatin (6 mg/kg, intravenously on day 1). Plasma samples were collected through a cannula placed on the external jugular vein at 0.5, 1, 2, 3, 4, 5, and 6 hours after gentamicin; the rats were sacrificed at 24 hours. Cisplatin caused a significant decrease in gentamicin excretion and an elevation of gentamicin levels in plasma, kidneys, liver, and spleen at all the time points that were tested, except with concomitant administration. Plasma urea nitrogen was elevated, and creatinine clearance decreased by the 4th day after cisplatin and these continued to be significantly different even on the 29th day after cisplatin.^ These results demonstrate that cisplatin nephrotoxicity reduced gentamicin excretion for at least a month in F-344 rats. This could increase the risk of toxicity from the second drug by elevating its levels in plasma and tissue. Thus, caution should be exercised when renally excreted drugs are given after cisplatin. ^

Maximal exercise hemodynamics and risk of mortality in apparently healthy men and women

The use of exercise electrocardiography (ECG) to detect latent coronary heart disease (CHD) is discouraged in apparently healthy populations because of low sensitivity. These recommendations however, are based on the efficacy of evaluation of ischemia (ST segment changes) with little regard for other measures of cardiac function that are available during exertion. The purpose of this investigation was to determine the association of maximal exercise hemodynamic responses with risk of mortality due to all-causes, cardiovascular disease (CVD), and coronary heart disease (CHD) in apparently healthy individuals. Study participants were 20,387 men (mean age = 42.2 years) and 6,234 women (mean age = 41.9 years) patients of a preventive medicine center in Dallas, TX examined between 1971 and 1989. During an average of 8.1 years of follow-up, there were 348 deaths in men and 66 deaths in women. In men, age-adjusted all-cause death rates (per 10,000 person years) across quartiles of maximal systolic blood pressure (SBP) (low to high) were: 18.2, 16.2, 23.8, and 24.6 (p for trend $<$0.001). Corresponding rates for maximal heart rate were: 28.9, 15.9, 18.4, and 15.1 (p trend $<$0.001). After adjustment for confounding variables including age, resting systolic pressure, serum cholesterol and glucose, body mass index, smoking status, physical fitness and family history of CVD, risks (and 95% confidence interval (CI)) of all-cause mortality for quartiles of maximal SBP, relative to the lowest quartile, were: 0.96 (0.70-1.33), 1.36 (1.01-1.85), and 1.37 (0.98-1.92) for quartiles 2-4 respectively. Similar risks for maximal heart rate were: 0.61 (0.44-0.85), 0.69 (0.51-0.93), and 0.60 (0.41-0.87). No associations were noted between maximal exercise rate-pressure product mortality. Similar results were seen for risk of CVD and CHD death. In women, similar trends in age-adjusted all-cause and CVD death rates across maximal SBP and heart rate categories were observed. Sensitivity of the exercise test in predicting mortality was enhanced when ECG results were evaluated together with maximal exercise SBP or heart rate with a concomitant decrease in specificity. Positive predictive values were not improved. The efficacy of the exercise test in predicting mortality in apparently healthy men and women was not enhanced by using maximal exercise hemodynamic responses. These results suggest that an exaggerated systolic blood pressure or an attenuated heart rate response to maximal exercise are risk factors for mortality in apparently healthy individuals. ^

Mutagenicity of herpes simplex virus type 1 in a shuttle vector

The shuttle vector plasmid pZ189 was used to find the kinds of mutations that are induced by herpes simplex virus type-1 (HSV-1). In cells infected by HSV-1 the frequency of mutation in supF gene, the mutagenesis marker, was increased over background by from two- to seven-fold, reaching 0.14-0.45%. No increase was induced by infection by vaccinia virus under the same conditions. Mutagenesis was an early event, showing a four-fold increase in mutation frequency at only two hours after infection, and peaking at a seven-fold increase at four hours after infection. DNA sequencing and gel electrophoresis analysis were performed on 105 HSV-1 induced mutants and 65 spontaneous mutants and provided the following information: (1) A change in plasmid size was seen in 54% of HSV-1 related mutants, compared with only 37% of spontaneous mutants. (2) Among point mutations, the predominant type was G:C to A:T transition, which accounted for 51% of point mutations in mutants isolated from cells infected with HSV-1, and 32% of point mutations in spontaneous mutants. (3) Deletions of DNA were seen in HSV-1 related mutants at a frequency of 40%, compared with 29% in spontaneous mutants. The HSV-1 related deletions were about half the length of spontaneous mutants and three contained short filler sequences. (4) Fifteen (15%) of HSV-1 induced mutants revealed the altered restriction patterns on agarose gel electrophoresis analysis and were due either to rearrangements of plasmid DNA, and/or to insertion of sequences derived from chromosomal DNA (seven plasmids). No insertions of DNA from HSV-1 were detected. Among spontaneous mutants, only 5 (7.7%) were rearrangements and none had inserted chromosomal DNA. (5) DNA sequence analysis of seven plasmids with inserted chromosomal DNA revealed that four cases had repetitive DNA sequences integrated and the other three were unidentified sequences from the GenBank database. Three repetitive DNA included $\alpha$ satellite, Alu and KpnI family sequences. The other sequence was identified as tRNA-like component. The observed mutations have implications for the mechanism of malignant transformation of cells by HSV-1. ^

Is sensitization to stimulants time dependent and mediated via NMDA receptors?

Chronic administration of psychomotor stimulants has been reported to produce behavioral sensitization to its effects on motor activity. This adaptation may be related to the pathophysiology of recurrent psychiatric disorders. Since disturbances in circadian rhythms are also found in many of these disorders, the relationship between sensitization and chronobiological factors became of interest. Therefore, a computerized monitoring system investigated the following: whether repeated exposure to methylphenidate (MPD) and amphetamine (AMP) could produce sensitization to its locomotor effects in the rat; whether sensitization to MPD and AMP was dependent on the circadian time of drug administration; whether the baseline levels of locomotor activity would be effected by repeated exposure to MPD and AMP; whether the expression of a sensitized response could be affected by the photoperiod; and whether MK-801, a non-competitive NMDA antagonist, could disrupt the development of sensitization to MPD. Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days served as baseline for each rat, and on day 3 each rat received a saline injection. The locomotor response to 0.6, 2.5, or 10 mg/kg of MPD was tested on day 4, followed by five days of single injections of 2.5 mg/kg MPD (days 5–9). After five days without injection (days 10–14) rats were re-challenged (day 15) with the same doses they received on day 4. There were three separate dose groups ran at four different times of administration, 08:00, 14:00, 20:00, or 02:00 (i.e. 12 groups). The same protocol was conducted with AMP with the doses of 0.3, 0.6, and 1.2 mg/kg given on day 4 and 15, and 0.6 mg/kg AMP as the repeated dose on days 5 to 9. In the second set of experiments only sensitization to MPD was investigated. The expression of the sensitized response was dose-dependent and mainly observed with challenge of the lower dose groups. The development of sensitization to MPD and ANT was differentially time-dependent. For MPD, the most robust sensitization occurred during the light phase, with no sensitization during the middle of the dark phase. (Abstract shortened by UMI.) ^

The association between maternal use of spermicides, condoms, intra-uterine devices or progesterone and major structural birth defects

Birth defects occur in 1 of every 33 babies born in the United States, and are the leading cause of infant death. Mothers using contraceptives that become pregnant may continue to use their contraceptives after their first missed menstrual period, thus exposing their baby in utero to the contraceptive product. Progesterone is also sometimes prescribed during the first trimester of pregnancy to mothers with a history of miscarriages or infertility problems. To ensure the safety of these products, it is important to investigate whether there is an increased occurrence of babies born with birth defects to mothers using various contraceptive methods or progesterone in early pregnancy. Using data from the National Birth Defects Prevention Study (NBDPS), an ongoing multi-state, population based case-control study, this study assessed maternal exposures to IUDs, spermicides, condoms and progesterone in early pregnancy. ^ Progesterone used for threatened miscarriage during the first three months of pregnancy was associated with an increased occurrence of hypoplastic left heart (adjusted odds ratios (OR) 2.24, 95% CI 1.13-4.21), perimembranous ventricular septal defects (OR 1.64, 95% CI 1.10-2.41), septal associations (OR 2.52, 95% CI 1.45-4.24), esophageal atresia (OR 1.82, 95% CI 1.04-3.08), and hypospadias (OR 2.12, 95% CI 1.41-3.18). Mothers using progesterone for injectable contraception had increased (OR > 2.5), but insignificant odds ratios for anencephaly, septal associations, small intestinal atresias and omphalocel. Progesterone used for fertility was not associated with an increased occurrence of any birth defects examined. ^ Mothers using progesterone for fertility assistance and threatened miscarriage were very similar with respect to their demographics and pregnancy history. They also both reported similar types of progesterone. Thus, if progesterone was a causal risk factor for birth defects we would have expected to observe similar increases in risk among mothers using progesterone for both indications. Because we predominantly observed increased associations among mothers using progesterone for threatened miscarriage but not fertility assistance, it is possible the increased associations we observed were confounded by indication (i.e. progesterone was administered for vaginal bleeding which occurred as a sequelae to the formation of a congenital anomaly. ^ No significant increased associations were observed between maternal spermicide use during pregnancy and 26 of 27 types of structural malformations. While multiple statistical tests were performed we observed first trimester maternal spermicide use to be associated with a significant increased occurrence of perimembranous ventricular septal defects (OR 2.21, 95% CI 1.16-4.21). A decreased occurrence (OR < 1.0) was observed for several categories of birth defects among mothers who conceived in the first cycle after discontinuing the use of spermicides (22 of 28) or male condoms (23 of 33). ^ Overall the percent of IUD use was similar between mothers of controls and mothers of all cases in aggregate (crude OR 1.05, 95% CI 0.61-1.84). Power was limited to detect significant associations between IUD use and birth defects, however mothers using an IUD in the month immediately prior to conception or during pregnancy were not associated with an increase of birth defects. Limb defects and amniotic band sequence previously reported to be associated with IUD use during pregnancy were not found to occur among any mothers reporting the use of an IUD during pregnancy.^

An empirical model to estimate the demand for primary care in urban settings

Objective. To measure the demand for primary care and its associated factors by building and estimating a demand model of primary care in urban settings.^ Data source. Secondary data from 2005 California Health Interview Survey (CHIS 2005), a population-based random-digit dial telephone survey, conducted by the UCLA Center for Health Policy Research in collaboration with the California Department of Health Services, and the Public Health Institute between July 2005 and April 2006.^ Study design. A literature review was done to specify the demand model by identifying relevant predictors and indicators. CHIS 2005 data was utilized for demand estimation.^ Analytical methods. The probit regression was used to estimate the use/non-use equation and the negative binomial regression was applied to the utilization equation with the non-negative integer dependent variable.^ Results. The model included two equations in which the use/non-use equation explained the probability of making a doctor visit in the past twelve months, and the utilization equation estimated the demand for primary conditional on at least one visit. Among independent variables, wage rate and income did not affect the primary care demand whereas age had a negative effect on demand. People with college and graduate educational level were associated with 1.03 (p < 0.05) and 1.58 (p < 0.01) more visits, respectively, compared to those with no formal education. Insurance was significantly and positively related to the demand for primary care (p < 0.01). Need for care variables exhibited positive effects on demand (p < 0.01). Existence of chronic disease was associated with 0.63 more visits, disability status was associated with 1.05 more visits, and people with poor health status had 4.24 more visits than those with excellent health status. ^ Conclusions. The average probability of visiting doctors in the past twelve months was 85% and the average number of visits was 3.45. The study emphasized the importance of need variables in explaining healthcare utilization, as well as the impact of insurance, employment and education on demand. The two-equation model of decision-making, and the probit and negative binomial regression methods, was a useful approach to demand estimation for primary care in urban settings.^

Prevalence and determinants of colonic polyps in children undergoing colonoscopy: A large hospital-based cross-sectional study

Background. Colorectal polyps are abnormal growths in the wall of the colon including the rectum. The study aims to estimate the prevalence and type of colonic polyps in children undergoing colonoscopic examination at Texas Children's Hospital (TCH) in Houston, Texas during 2000-2007. Also, to examine the factors associated with colonic polyps and the potential determinants of colonic polyps in children undergoing colonoscopy and compare those who had colonic polyps with those who did not on colonoscopy, and determine the significant risk factors of colonic polyps in these children. ^ Methods. We conducted a cross sectional study to analyze data collected at TCH. We obtained demographic, clinical, and histopathology information on consecutive patients who underwent colonoscopy during 2000-2007 from endoscopic records contained in the PEDS-CORI registry (Pediatric Endoscopy Database System-Clinical Outcomes Research Initiative), and abstracted data from the accompanying histopathology reports. ^ Results. We identified 2,693-unique patients, under 18 years of age, who underwent colonoscopy. Approximately 65.5% were white non-Hispanic, and 10.8% African-American. The mean age was 8.7 years and 51.8% were female patients. Polyps were present in 174 patients (6.5%). The most common two histological types were juvenile (60.6%), inflammatory (17.4%). We found that the prevalence of polyps was higher in younger aged children (12.9% in 0-5 years) than in older aged children (4% in 15-17 years), and slightly higher in males than in females (7.9% and 5.4% respectively). For males only, the odds of polyps were statistically significantly higher in Blacks and Hispanics compared to white non Hispanics (OR of 2.2 and 2.1, respectively, and 95% CI of 1.3, 3.9 and 1.3, 3.5 respectively). The indications for colonoscopy were different for children with polyps compared to those without polyps, i.e., 47.0% vs. 19.8% respectively for lower GI bleeding, 2.7% vs. 21.4% respectively for abdominal pain/bloating, and, or 0.9% vs. 9.6% respectively for diarrhea. ^ Conclusion. Colorectal polyps occur in about 1 in 15 children and adolescents undergoing first colonoscopy. The demographic variable of younger age is strongly associated with having polyps irrespective of ethnicity. Lower GI bleeding is strongly related to the presence of colorectal polyps in children and adolescents undergoing colonoscopy.^