The Induction Profile of Three Orally Active Imidazopyridine-Containing Cardiotonic Agents in Rat Hepatic Microsomes

The Induction Profile of Three Orally Active Imidazopyridine-ContainingCardiotonic Agents in Rat Hepatic Microsomes. BERNSTEIN, J.R, AND FRANKLIN, R. B., (1986). Fundam Appl. Toxicol. 7, 26-32.The induction of hepatic cytochrome P-450-linked monooxygenaseshas been studied after the twice daily, oral administrationof two imidazo[4,5-c]pyridine-containing compounds and one imidazo[4,5-6]pyridine-containingdrug. The compounds were administered by the oral route, atdifferent doses, for 6 days after which time hepatic microsomeswere prepared. In vitro biochemical assays revealed that allthree compounds increased the O-deethylation of 7-ethoxyresorufinin a dose-dependent manner while not significantly affectingeither the 0-de- alkylation of 7-ethoxycoumarin or the levelsof NADPH-cytochrome c reductase. Ethylmorphine- N-demethylationwas decreased after dosing with the imidazo[4,5-b]pyridine-containingdrug. Levels of cytochrome(s) P-450 and liver-to-body weightratios were not significantly altered. The imidazo[4,5-c]pyndine-containingcompound was more potent in terms of the induction of 7-ethoxyresorufinthan either of the imidazo[4,5-c]pyridine-containing compoundsbut was approximately fourfold less active in this regard than3-methylcholanthrene. No induction of cy- tochrome-.P-450-linkedmonooxygenase activities was evident at a twice daily dose of5 mg/kg for 6 days for all three compounds tested, constitutinga no-effect level. The imidazo[4.5-c]pyridine-1 containing compoundsexhibited modified Type II difference spectra when added toa suspension of rat hepatic microsomes. The imidazo[4,5-6]pyridine-containingcompound has previously been reported to be (i) a rapid andpotent inducer of monooxygenase activity and (ii) have a TypeII difference Spectrum.(c) 1986 Society of Toxicology     

In Vitro Percutaneous Absorption of Cadmium from Water and Soil into Human Skin

The objective was to determine percutaneous absorption of cadmiumas the chloride salt from water and soil into and through humanskin. Soil (Yolo County 65-California-57-8) was passed through10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixedwith radioactive cadmium-109 at 13 ppb. Water solutions of cadmium-109at 116 ppb were prepared for comparative analysis. Human cadaverskin was dermatomed to 500-µm, and used in glass diffusioncells with human plasma as the receptor fluid (3 ml/hr flowrate) for a 16-hr skin application time. Cadmium in water (5µ1/cm²) penetrated skin to concentrations of 8.8 ±0.6 and 12.7 ± 11.7% of the applied dose from two humanskin sources. Percentage doses absorbed into plasma were 0.5± 0.2 and 0.6 ± 0.6%, respectively. Cadmium fromsoil (0.04 g soil/cm²) penetrated skin at concentrations of0.06 ± 0.02 and 0.13 ± 0.05% for the two humanskin sources. Amounts absorbed into plasma were 0.01 ±0.01 and 0.07 ± 0.03%. Most of the non-absorbed cadmiumwas recovered in the soap and water skin surface wash. Bindingof cadmium from water to soil was greater than binding fromwater to powdered human stratum corneum, supporting the lowerabsorption from soil than from water. Short-term exposure ofcadmium in water to human skin for 30 min (bath or swim) resultedin skin uptake, which upon further perfusion (48 hr), absorbedinto the plasma receptor fluid (systemic). Cadmium in soil wasincreased from 6.5 to 65 ppb. Skin levels correspondently increased,but plasma receptor fluid levels remained constant. Soil capacitywas decreased from 40 to 4 mg/cm². Skin levels correspondinglydecreased, suggesting decreased skin contact, but plasma receptorfluid levels remained constant. The above suggest that, within vitro diffusion, the surface concentration of cadmium willinfluence skin cadmium concentration, but that absorption intoplasma receptor fluid is relatively independent of skin surfaceconcentrations. Calculations suggest that a daily whole bodyexposure to cadmium at 116 ppb with 0.5% absorption will resultin daily systemic intake of about 10 µg Cadmium.     

CONTINUOUS COLLECTION OF PULSE OXIMETRY DATA: A NEW, INEXPENSIVE, PORTABLE COMPUTERIZED METHOD

The availability of reliable pulse oximetry equipment has ledto interest in identifying patterns of hypoxaemia in the postoperativeperiod. Methods for the computerized collection and analysisof pulse oximetry data have been described, but these requirecontinuous use of a relatively powerful computer system throughoutboth the monitoring (data collection) and analysis periods.We have designed a technique which uses a small, portable andrelatively inexpensive computer unit for data collection, afterwhich the data may be transferred to a more powerful computerfor analysis. Appropriate programming and choice of softwarehave produced a relatively "user friendly " system which canbe operated successfully even with minimal computing experience.The unit has the potential to be modified to form the basisof a "medical advice system " which could be used for the "intelligent"monitoring of high risk patients.     

COMPARISON OF THE NEUROMUSCULAR BLOCK INDUCED BY MIVACURIUM, SUXAMETHONIUM OR ATRACURIUM DURING NITROUS OXIDE-FENTANYL ANAESTHESIA

We compared the neuromuscular and cardiovascular changes followingadministration of mivacurium 0.15, 0.20 and 0.25 mg kg^–1,suxamethonium 1.0 mg kg^–1 or atracurium 0.5 mg kg^–1i.v. in 41 (ASA physical status I or II) patients during nitrousoxide—fentanyl anaesthesia. Mean onset times for totalablation of twitch response for mivacurium 0.15, 0.20 and 0.25mg kg^–1, were 2.5, 2.4 and 2.7 min, respectively, similarto that for atracurium (2.5 min), but longer than for suxamethonium(1.1 min) (P < 0.05). Mean times from administration of druguntil twitch response recovered to 10% of control were shorterfor each dose of mivacurium (15.6, 18.0 and 20.6 min, respectively)than for atracurium (40.0 min) and longer than for suxamethonium(7.7 min) (P < 0.05). Mean infusion rate required to maintaintwitch response at 5±4% control was 6.7 µg kg^–1min^–1 for mivacurium and 6.3 µg kg^–1 min^–1for atracurium. Following neostigmine 0.045 mg kg^–1, meantimes for twitch tension to recover from 10% to 90% of controlwere similar for mivacurium (9.7 min) and atracurium (10.5 min).Transient decreases in mean arterial pressure (> 20%) wereobserved in seven of 15 patients who received the two higherdoses of mivacurium. Presented in part at the Annual Scientific Meeting of the AmericanSociety of Anesthesiologists, San Francisco, October 1988.     

Zidovudine Toxicity to Cats Infected with Feline Leukemia Virus

Zidovudine Toxicity to Cats Infected with Feline Leukemia Virus.HASCHEK, W. M., WEIGEL, R. M., SCHERBA, G., DEVERA, M. C, FEINMEHL,R., SOLTER, P., TOMPKJNS, M. B., AND TOMPKINS, W. A. F. (1990).Fundam. Appl. Toxicol. 14, 764–775. Feline leukemia virus(FeLV) infection of cats is a model for the acquired immunodeficiencysyndrome in humans. The toxicity of zidovudine was evaluatedin SPF cats experimentally infected with FeLV. At initiationof the zidovudine study, all cats were antibody positive forFeLV antigens but clinically asymptomatic. Four cats were alsoviremic. Thirteen, 6- to 10-month-old cats were divided intofive dosage groups and given zidovudine po at 0, 7.5, 15, 30,or 60 mg/kg daily in three equally divided doses for 32 to 34days. Titers of circulating virus antigen remained constant;however, three of six cats receiving the higher doses of zidovudine(30 mg/kg) showed an increase in antibody titers to FeLV. Administrationof zidovudine resulted in a progressive anemia, dependent upondose and time. Macrocytes were observed prior to the developmentof anemia and were also found in several nonanemic cats. Repeatedmeasures regression analyses indicated that an increased doseof zidovudine was associated with decreased packed cell volume,red blood cell count, and hemoglobin. As determined from thepacked cell volume, the analyses indicate that anemia is inducedonly by the two highest doses of zidovudine. The regressionmodel indicates that daily doses of 60 and 30 mg/kg are expectedto induce anemia by Day 4 and Day 13, respectively. Progressiveabsolute neutropenia was observed in the 30 mg/kg groups. Histopathologiclesions consisted of marked bone marrow hypercellularity incats given 30 mg/kg zidovudine and splenic extramedullary hematopoiesisin cats given 15 mg/kg. Thus, oral toxicity of zidovudine inthe cat is manifested by a dose-related anemia and neutropeniaas observed in humans.     

Synergistic Effects of Inward Rectifier (IK1) and Pacemaker (If) Currents on the Induction of Bioengineered Cardiac Automaticity

Introduction: Normal heart rhythms originate in the sinoatrial node. HCN‐encoded funny current (I_f) and the Kir2‐encoded inward rectifier (I_K1) counteract each other by respectively oscillating and stabilizing the negative resting membrane potential, and controlling action potential firing. Therefore, I_K1 suppression and I_f overexpression have been independently exploited to convert cardiomyocytes (CMs) into AP‐firing bioartificial pacemakers. Although the 2 strategies have been largely assumed synergistic, their complementarity has not been investigated. Methods and Results: We explored the interrelationships of automaticity, I_f and I_K1 by transducing single left ventricular (LV) CMs isolated from guinea pig hearts with the recombinant adenoviruses Ad‐C MV‐G FP‐I RES‐HCN1‐ÄÄÄ and/or Ad‐CGI‐Kir2.1 to mediate their current densities via a whole‐cell patch clamp technique at 37°C. Results showed that Ad‐CGI‐HCN1‐ÄÄÄ but not Ad‐CGI‐Kir2.1 transduction induced automaticity (181.1 ± 13.1 bpm). Interestingly, Ad‐CGI‐HCN1‐ÄÄÄ/Ad‐CGI‐Kir2.1 cotransduction significantly promoted the induced firing frequency (320.0 ± 15.8 bpm; P < 0.05). Correlation analysis revealed that the firing frequency, phase‐4 slope and APD₉₀ of AP‐firing LV CMs were correlated with I_f (R² > 0.7) only when ?2 >I_K1 >?4 pA/pF but not with I_K1 over the entire I_f ranges examined (0.02 < R² < 0.4). Unlike I_f, I_K1 displayed correlation with neither the phase‐4 slope (R²= 0.02) nor phase‐4 length (R²= 0.04) when ?2 > I_f > ?4 pA/pF. As anticipated, however, APD₉₀ was correlated with I_K1 (R²= 0.4). Conclusion: We conclude that an optimal level of I_K1 maintains a voltage range for I_f to operate most effectively during a dynamic cardiac cycle.     

Heart Rhythm During Syncope and Presyncope: Results of Implantable Loop Recorders

NIEROP, P.R., et al. : Heart Rhythm During Syncope and Presyncope: Results of Implantable Loop Recorders. Ambulatory ECG monitoring in patients with recurrent syncope is nondiagnostic in the majority of cases. Recently, an ECG implantable loop recorder (ILR) has been introduced. The ILR performs continuous ECG monitoring over a period of at least 14 months. From February 1997 to September 1999, 35 patients underwent implantation of an ILR. During a mean follow-up of  11 ± 8 months  , 24 (69%) patients had recurrent syncope or presyncope events. Four (11%) patients were not capable of activating the ILR to save the event. A symptom-rhythm correlation could be studied in 20 (83%) of 24 patients. Forty of 44 recurrences were captured by the ILR. There were 14 (40%) patients with at least one syncopal episode. An arrhythmic cause for syncope was found in eight of them (bradycardia in four and tachycardia in four). In the other six patients the heart rhythm was normal. In 17 (49%) patients with 1-year follow-up, the mean syncope event rate 12 months before ILR implantation was  4.7 ± 2.4  , whereas the mean syncope event rate 12 months after ILR implantation was  1.3 ± 0.7  (  P < 0.01  ). Resolution of symptoms was observed in 6 (17%) patients. These patients were significantly younger than patients without resolution (  50 ± 18 vs 69 ± 14 years, p < 0.01  ) and five were women. Three (9%) patients died during follow-up, all of them were noncompliant during their follow-up. In conclusion, the ILR made symptom—rhythm correlation possible in 83% of patients with recurrent syncope. Syncope recurrences decreased significantly after implantation of the device, especially in the younger patients. Noncompliant patients had a high mortality rate.     

Intravenous Amiodarone Suppression of Electrical Storm Refractory to Chronic Oral Amiodarone

We report the case of an electrical storm in a cardiac arrest survivor with an ICD, in whom chronic oral amiodarone failed to suppress ventricular arrhythmias, and in whom intravenous amiodarone resulted in stability for 6 weeks prior to successful cardiac transplantation. Intravenous amiodarone can be successful in suppressing life-threatening ventricular arrhythmias, even when chronic oral amiodarone is unsuccessful.     

Hepatitis B Antigen and Antibody in Heroin Users

Hepatitis B surface antigen (HBsAg) and antibody (anti-HBsAg) were determined on 442 asymptomatic heroin users and 246 controls. Of the drug-taking group, 124 used heroin intravenously and 318 nonintravenously (smoking, sniffing). Twenty-three (5.2%) heroin users were HBsAg positive and 118 (26.7%) anti-HBsAg positive, compared to three (1.2%) HBsAg positive and 28 (11.4%) anti-HBsAg positive controls, both statistically significant. HBsAg was positive in eight (6.5%) intravenous heroin users and statistically identical to 15 (4.7%) HBsAg positive nonintravenous users. Positive anti-HBsAg in 55 (44.4%) intravenous heroin users compared to 63 (19.8%) nonintravenous users, however, is statistically significicant.