Effectiveness of dentine bonding agents against cariogenic bacteria in vitro: a comparison of two methods.

Data obtained from studies on the antimicrobial properties of bonding agents are the subject of controversy, probably because of methodological differences. This study compared two commonly used in vitro methods, the disc agar diffusion test and the well agar diffusion test. Agar plates were seeded with Streptococcus sobrinus, Lactobacillus gasseri, or Actinomyces naeslundii. For the well diffusion test, wells cut out of the agar were filled with the test material, and for the disc method, discs impregnated with the test material were applied to the agar; the discs and wells were both 9 mm in diameter. After incubation, measurements of the zones of inhibition showed little agreement between the two methods when bonding agents were tested; the mean differences (+/- sdiff) in the zones of inhibition between the methods were 0.7 +/- 3.4 mm (P = 0.40, one sample t-test against zero), 4.9 +/- 4.4 mm (P = 0.97), and 0.8 +/- 4.3 mm (P = 0.47) for S. sobrinus, L. gasseri, and A. naeslundii, respectively. Mean differences were less contrasting when chlorhexidine and pure components were tested (P < 0.05 for S. sobrinus and L. gasseri). These results indicate the need for a gold standard method to evaluate the antimicrobial properties of bonding agents.

Chloride-sensitive renal microangiopathy in the stroke-prone spontaneously hypertensive rat.

BACKGROUND: In the stroke-prone spontaneously hypertensive rat (SHRSP) fed a low-normal NaCl diet, we recently reported that supplemental KCl, but not KHCO(3) or K-citrate (KB/C), exacerbated hypertension and induced hyperreninemia and strokes. We now ask the following question: In these SHRSP, is either such selectively Cl(-)-sensitive hypertension or hyperreninemia a pathogenetic determinant of renal microvasculopathy? METHODS: SHRSPs were randomized to either supplemental KCl, KB/C, or nothing (control) at 10 weeks of age. Four and 14 weeks afterward, we assessed renal microangiopathy histologically and measured plasma renin activity (PRA). From randomization, blood pressure was measured radiotelemetrically and continually; proteinuria was measured periodically. RESULTS: KCl, but not KB/C, amplified renal microangiopathy and proteinuria. Four weeks after randomization, when KCl initially exacerbated hypertension, renal microangiopathy, hyperproteinuria, and hyperreninemia had not yet occurred. However, across all groups, the increment of SBP at four weeks strongly predicted its final increment, severity of renal microangiopathy, proteinuria, and PRA 14 weeks after randomization. Then, the severity of renal microangiopathy varied directly with the levels of systolic blood pressure (SBP; R(2) = 0.9, P < 0.0001), PRA (R(2) = 0.7, P < 0.0001), and proteinuria (R(2) = 0.8, P < 0.0001) as continuous functions across all treatment groups. Renal creatinine clearance was greater with KB/C. CONCLUSIONS: In the SHRSP, (1) like cerebral microangiopathy, renal microangiopathy is selectively Cl(-) sensitive and hence, systemic microangiopathy is as well; (2) Cl(-) likely amplifies microangiopathy by exacerbating hypertension and possibly also by increasing PRA; and (3) Cl(-) might increase blood pressure and PRA by further constricting the renal afferent arteriole.

Differing effects of supplemental KCl and KHCO3: pathophysiological and clinical implications.

Compared to the prehistoric diet, the modern human diet contains not only excessive NaCl and deficient K+, but also deficient precursors of HCO3- and sometimes excessive precursors of nonvolatile acid. The mismatch between the modern diet and the still ancient biological machinery of humans subtly but chronically disorders their internal milieu, giving rise to a prolonged state of low-grade potassium deficiency and low-grade metabolic acidosis whose severity increases with age. Supplemental KCI cannot redress this mismatch and correct this state. However, the mismatch is redressed and the state corrected by restoring intakes of K+ and HCO3- to levels approaching those in the diet of our prehistoric forebearers, with either fruits and vegetables or with supplemental KHCO3. So restored, KHCO3 can: 1) attenuate hypertension and possibly prevent its occurrence by suppressing the phenomenon of normotensive NaCl-sensitivity, in part by its natriuretic effect; (2) prevent kidney stones by reducing urinary excretion of calcium and increasing urinary excretion of citrate; (3) ameliorate and protect against the occurrence of osteoporosis by increasing the renal retention of calcium and phosphorus, and by suppressing bone resorption and enhancing bone formation; and (4) likely prevent stroke.

Normotensive salt sensitivity: effects of race and dietary potassium.

-Normotensive salt sensitivity, a putative precursor of hypertension, might be quite frequent in African Americans (blacks) and less frequent in Caucasian Americans (whites), but only when dietary potassium is deficient and not when maintained well within the normal range. We tested this hypothesis in 41 metabolically controlled studies of 38 healthy normotensive men (24 blacks, 14 whites) who ate a basal diet low in sodium (15 mmol/d) and marginally deficient in potassium (30 mmol/d) for 6 weeks. Throughout the last 4 weeks, NaCl was loaded (250 mmol/d); throughout the last 3, potassium was supplemented (as potassium bicarbonate) to either mid- or high-normal levels, 70 and 120 mmol/d. Salt sensitivity, defined as an increase in mean arterial blood pressure >/=3 mm Hg with salt loading, was deemed "moderate" if increasing

NaCl-induced renal vasoconstriction in salt-sensitive African Americans: antipressor and hemodynamic effects of potassium bicarbonate.

In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9+/-3.5 (mean+/-SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K+) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K+ was supplemented to 170 mmol/d (KHCO3). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (DeltaMAP >+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m2) decreased from 920+/-75 to 828+/-46 (P<0.05); filtration fraction (FF, %) increased from 19. 4+/- to 21.4 (P<0.001); and renal vascular resistance (RVR) (10(3)xmm Hg/[mL/min]) increased from 101+/-8 to 131+/-10 (P<0.001). In all subjects combined, DeltaMAP varied inversely with DeltaRBF (r =-0.57, P=0.02) and directly with DeltaRVR (r = 0.65, P=0.006) and DeltaFF (r = 0.59, P=0.03), but not with MAP before NaCl loading. When supplemental KHCO3 abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K+-deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO3, GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity.

NMR spectroscopy and MRI investigation of a potential bioartificial liver.

NMR feasibility was established for a coaxial hydrophobic-membrane bioreactor containing isolated rat hepatocytes with features designed to mimic the human liver. A novel triple-tuned NMR probe and a perfusion system controlling temperature, gas concentrations, flow-rate, and pH were used. We determined the optimum coaxial interfiber distance (i.e. diffusion distance) for maintaining hepatocyte viability in two bioreactor prototypes. Prototype no. 1 and no. 2 had diffusion distances of 500 microns and 200 microns, respectively. Cell viability was established by 31P NMR and trypan blue exclusion. Only prototype no. 2 maintained cell viability for more than 6 h, indicating the importance of diffusion distance. 31P spectra obtained over this 6 h time period were similar to in vivo spectra of rat liver. The 31P spectra were found to be more sensitive to subacute cell viability than trypan blue exclusion. In the 1H and 31P spectra, 1H2O and inorganic phosphate signals were split in two at all flow-rates, probably due to bulk magnetic susceptibility effects originating from the three bioreactor compartments. MRI was useful for quality control and determining flow dynamics, fiber integrity, and cell inoculate distribution. MRI revealed that the inner fibers were not centered in either prototype. Although an increased flow-rate did not influence spectral resolution or chemical shifts, significant degradation of MRI quality occurred above 50 mL/min. NMR spectroscopy and imaging provide valuable, real-time information on cell biochemistry and flow dynamics which can be used in development and monitoring of bioreactors designed as artificial livers.

Reduced dietary potassium reversibly enhances vasopressor response to stress in African Americans.

Acute vasopressor responses to stress are adrenergically mediated and hence potentially subject to differential modulation by dietary potassium and sodium. The greater vasopressor responsiveness in blacks compared with whites might then be consequent not only to a high dietary salt intake but also to a marginally reduced dietary potassium intake. Under controlled metabolic conditions, we compared acute vasopressor responses to cold and mental stress in black and white normotensive men during three successive dietary periods: (1) while dietary potassium was reduced (30 mmol K+/70 kg per day) and salt was restricted (10 to 14 days); (2) while salt was loaded (15 to 250 mmol Na+/70 kg per day) (7 days); and (3) while salt loading was continued and potassium was either supplemented (70 mmol K+/70 kg per day) (7 to 21 days) in 9 blacks and 6 whites or continued reduced (30 mmol K+/70 kg per day) (28 days) in 4 blacks (time controls). At the lower potassium intake, cold-induced increase in forearm vascular resistance in blacks was twice that in whites during both salt restriction and salt loading. Normalization of dietary potassium attenuated cold-induced increases in both forearm vascular resistance and systolic and diastolic blood pressures in blacks but only in systolic pressure in whites. In blacks but not in whites, normalization of dietary potassium attenuated mental stress-induced increases in systolic and diastolic pressures. In normotensive blacks but not whites, a marginally reduced dietary intake of potassium reversibly enhances adrenergically mediated vasopressor responsiveness to stress. That responsiveness so enhanced over time might contribute to the pathogenesis of hypertension in blacks.

Genetically determined chloride-sensitive hypertension and stroke.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a genetically determined model of "salt-sensitive" stroke and hypertension whose full phenotypic expression is said to require a diet high in Na+ and low in K+. We tested the hypothesis that dietary Cl- determines the phenotypic expression of the SHRSP. In the SHRSP fed a normal NaCl diet, supplementing dietary K+ with KCl exacerbated hypertension, whereas supplementing either KHCO3 or potassium citrate (KB/C) attenuated hypertension, when blood pressure (BP) was measured radiotelemetrically, directly and continually. Supplemental KCl, but not KB/C, induced strokes, which occurred in all and only those rats in the highest quartiles of both BP and plasma renin activity (PRA). PRA was higher with KCl than with KB/C. These observations demonstrate that with respect to both severity of hypertension and frequency of stroke the phenotypic expression of the SHRSP is (i) either increased or decreased, depending on whether the anionic component of the potassium salt supplemented is, or is not, Cl-; (ii) increased by supplementing Cl- without supplementing Na+, and despite supplementing K+; and hence (iii) both selectively Cl--sensitive and Cl--determined. The observations suggest that in the SHRSP selectively supplemented with Cl- the likelihood of stroke depends on the extent to which both BP and PRA increase.

The effects of aging on the electrophysiologic and hemodynamic responses to nifedipine in isolated perfused hearts.

Age effects on responses to calcium channel blockade with nifedipine were studied in isolated Langendorff-perfused Fischer 344 rat hearts. Responses to 25 min of perfusion with nifedipine concentrations of 0, 25, 50, 75, and 100 ng/ml were studied in hearts from 11 mature (6 months) and 13 senescent (23-27 months) male F344 rats. Nifedipine produced significant increases in the atrial cycle length (p less than 0.001), paced atrioventricular (AV) conduction time (p less than 0.001), AV Wenckebach cycle length (p less than 0.001), left ventricular (LV) diastolic pressure (p less than 0.001), and decreases in LV systolic pressure (p less than 0.001) and peak dP/dt (p less than 0.001) in hearts from both mature and senescent rats. Greater decreases in the atrial rate (p less than 0.05) and depression of peak dP/dt (p less than 0.05) were detected in senescent vs. mature rat hearts. No age difference in responses of AV conduction parameters were detected although increases in the AV Wenckebach cycle length appeared to be greater in senescent hearts at concentrations greater than 75 ng/ml.

Effects of physiological aging on cardiac electrophysiology in perfused Fischer 344 rat hearts.

Aging effects on heart rate and atrioventricular (AV) conduction were studied in Langendorff-perfused hearts from 18 mature (4-6 mo), 12 middle-aged (12-14 mo), and 18 senescent (24-26 mo) Fischer 344 rats. Heart rate decreased with increasing age from 218 +/- 18 in mature to 196 +/- 27 (mean +/- SD) beats/min in middle-aged rats to 183 +/- 22 beats/min in senescent rats (analysis of variance, P less than 0.001). Spontaneous AV conduction time increased from 43 +/- 7 to 49 +/- 5 to 62 +/- 9 ms with aging (P less than 0.0001). Paced AV conduction time also lengthened with aging, and AV Wenckebach block cycle length increased from 122 +/- 10 to 133 +/- 9 to 152 +/- 16 ms (P less than 0.005). Intra-atrial conduction time was unaffected by age. Age differences in heart rate and AV conduction responses to isoproterenol (0.5 x 10(-9) to 1 x 10(-7) M) were noted with greater sensitivity at lower doses in hearts from younger rats. In separate experiments, 18 mature and 19 senescent Fischer 344 rats received reserpine (0.25 mg.kg-1.day-1 ip) for 6 days before study. Age differences in heart rate and AV conduction persisted (P less than 0.0001). Histopathological examination of AV nodal and His-bundle tissues in three hearts from each age group showed increased intercellular collagen with advancing age.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of aging on the electrophysiologic responses to verapamil in isolated perfused rat hearts.

The effects of aging on heart rate and atrioventricular (AV) conduction responses to verapamil (0-100 ng/ml) were studied in Langendorff perfused hearts from 12 mature (4-6 months) and 12 senescent (24 months) male Fischer 344 rats and in hearts from 10 mature and 9 senescent rats after reserpine administration (0.25 mg/kg/day i.p. for 5-7 days). During 30 min of perfusion with verapamil concentrations of 0, 10, 20, 50 and 100 ng/ml in the absence of reserpine administration, intervals between atrial electrograms (A-A intervals), paced AV conduction time and AV Wenckebach cycle lengths increased in hearts from all animals (P less than .001). A-A intervals increased more in senescent vs. mature animals (with marked slowing in 3/12 senescent and 0/12 mature at 100 ng/ml), spontaneous AV Wenckebach block occurred more frequently in hearts from senescent animals (in 7/12 senescent and 1/12 mature, P less than .07) and AV Wenckebach cycle length increased more in senescent vs. mature hearts (from 123 +/- 11 to 294 +/- 108 msec, mean +/- S.D., in mature vs. 154 +/- 16 to 458 +/- 10 msec in senescent hearts). Reserpine administration did not significantly alter qualitative responses to verapamil, but accentuated age differences in responses at higher verapamil concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

[Short-term dobutamine therapy in severe cardiac insufficiency]. / Dobutamin-Kurztherapie bei schwerer Herzinsuffizienz.

The feasibility of heart transplantation has stimulated new interest in the therapy of severe refractory congestive heart failure even as an interim solution. We studied the hemodynamics, clinical efficacy and practical implications of a 72-hour dobutamine infusion in 11 patients with NYHA IV refractory congestive heart failure (age 40-73, average 55 years). The dose was 250-1000 micrograms/min, with the goal of increasing cardiac output by 30-50%. Changes in the pharmacokinetics of lidocaine were studied by single dose kinetics in 7 patients. Cardiac output increased from 2.94 +/- 0.68 to 4.77 +/- 1.1 l/min and stroke volume from 35 +/- 10 to 56 +/- 12 ml (p less than 0.001). Pulmonary capillary wedge pressure decreased from 28.5 +/- 5 to 21 +/- 6 and central venous pressure from 14 +/- 6 to 7 +/- 3 mm Hg (p less than 0.007). There was marked worsening of hemodynamics 24-48 h after starting dobutamine. However, after withdrawal of dobutamine a significantly higher cardiac output and stroke volume (3.73 +/- 0.43 l/min, 42 +/- 7 mm Hg. p less than 0.05) persisted. Both clearance and distribution volume of lidocaine increased, while half life decreased significantly (6.61 +/- 1.43 to 5.33 +/- 0.77 h. p less than 0.05). 9 of 11 patients developed Lown IVb ventricular arrhythmia, while in 4 massive diuresis occurred necessitating volume substitution. 6 patients left hospital clinically improved, 2 were transplanted and 3 patients died 1 day to 3 weeks after ending dobutamine. Dobutamine had salutary hemodynamic and clinical effects outlasting the duration of dobutamine therapy. Due to its arrhythmogenic effects it should be administered under ECG monitoring. In patients treated with lidocaine, upward dose adjustments may be necessary with improving hemodynamics.

Predictability and intraindividual variability of serum theophylline concentrations in patients with obstructive lung disease: 12-h versus 24-h dosing.

The predictability and intraindividual variability of serum theophylline concentrations (STC) after different dosing schedules were investigated in 24 patients with chronic obstructive lung disease (COLD). Three oral regimens were compared in 3 groups of 8 randomly assigned patients. Group I:Drug A once daily in the evening; Group II: Drug A b.d.; Group III: Drug B b.d. The doses for each patient were estimated by Bayesian forecasting aiming at an STC of 10-15 mg/l. STC and FEV1 were measured on two consecutive days at steady-state. The day-to-day variability of STC was less than 20% in all three groups. The within-day fluctuation in Group I amounted to 259% (median) compared to 57% and 38% in Groups II and III, respectively. Dose adjustment by Bayesian forecasting resulted in a therapeutic STC in most patients with a b.d. regimen, whereas for the once daily dose the prediction was not satisfactory. No difference in lung function was found between the 24-h and 12-h dosing, probably because of the large intersubject variability in FEV1. Therefore, the question whether the differences in STC profile are of clinical importance in COLD can only be investigated in a larger group of patients.

Computer-assisted individualized lidocaine dosage: clinical evaluation and comparison with physician performance.

The performance of a computerized dosing aid in achieving a target serum concentration of lidocaine in the middle of the recommended therapeutic range (3.5 mg/L) was evaluated in 63 patients treated for acute ventricular arrhythmias. In all patients a serum concentration measurement was obtained shortly after starting lidocaine infusion. In 22 patients a microcomputer program based on a Bayesian forecasting technique was used for dosing recommendations, whereas in 41 the serum concentration was interpreted and the dose was adjusted by the unaided physician. Both groups were similar with respect to the average concentration achieved (control: 3.8 +/- 1.13 [SD] mg/L, computer-aided: 3.5 +/- 0.59 mg/L). However, the interindividual variability was significantly larger in the control group (95% confidence interval: 1.5 to 6.1 mg/L vs 2.3 to 4.7 mg/L [p less than 0.01]). Nine of the 41 patients in the control group had a lidocaine concentration outside the recommended therapeutic range of 2 to 5 mg/L compared to only 1 of 22 in the computer-aided group. Lidocaine concentrations greater than 2 mg/L were associated with significantly more effective suppression of ventricular arrhythmias (p less than 0.05). The results show that Bayesian forecasting outperforms the physician in early adjustment of lidocaine dosage based on serum concentration measurements.

Once a day verapamil in essential hypertension.

Pharmacodynamic and therapeutic studies with a new slow release 240 mg verapamil formulation were performed in a total of 73 patients with essential hypertension (WHO I-II, diastolic greater than or equal to 100 mm Hg). Chronic administration of slow release 240 mg verapamil, one or two tablets in the morning, resulted in 24 h plasma concentration profiles with trough levels greater than 40 ng ml-1 in 14 of 16 patients and good 24 h blood pressure control. There was no correlation between plasma verapamil or norverapamil concentration and blood pressure response. Monotherapy with slow release verapamil was well tolerated and resulted in good blood pressure control (less than or equal to 95 mm Hg diastolic) in 46 of the 57 patients. Responses were best in older patients and those with low plasma renin or higher control blood pressure. Slow release 240 mg verapamil given once daily is a simple and effective regimen.

Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. II: Pharmacodynamics.

This study determined the kinetics of the effects of atropine on heart rate and saliva flow in three healthy male volunteers after intravenous administration of 1.35 and 2.15 mg of the drug. The pharmacokinetics of atropine and its primary metabolite, tropine, were determined simultaneously. Both the pharmacokinetic and effect data were fitted to an integrated kinetic-dynamic model. The maximum heart rate and minimum saliva flow occurred with a significant delay of 7-8 min after drug administration. Both effects were nonlinearly related to the amount of drug in the peripheral compartment. Maximum heart rates of 192 and 217% of the control values were observed at the lower and higher dose levels, respectively. Minimum saliva flows of 8 and 3% of the control values were measured after the lower and higher doses of atropine, respectively. The time durations of the positive chronotropic effect of the drug were 170 and 250 min at the lower and higher dose levels, respectively; the corresponding values for the length of the antisialogogue effect of the drug were 230 and 340 min, respectively.

Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. I: Pharmacokinetics.

The pharmacokinetics of atropine in three healthy male volunteers after intravenous administration of 1.35 and 2.15 mg of the drug was determined. Pharmacodynamic effects of atropine were measured simultaneously. All the data were fitted to a novel integrated kinetic-dynamic model. Plasma concentrations of atropine and the amounts of atropine and its primary metabolite, tropine, excreted in the urine were measured by a sensitive gas chromatographic-mass spectrometric assay. The kinetics of elimination of atropine was first order. There was evidence that the kinetics of distribution of the drug was dose dependent. Two phases with apparent half-lives of 1 and 140 min were distinguishable in accordance with a linear two-compartment disposition model for atropine. The urinary excretion of unchanged drug was 57% of the dose. The steady-state volume of distribution was 210 L, implying extensive tissue binding and/or partitioning. Renal plasma clearance was 660 mL/min, suggesting significant tubular secretion. The renal clearance of atropine depended on urine flow. Urinary excretion of tropine amounted to 29% of the dose. The kinetics of the metabolite was first order.

Quantitative relationships between structure and pharmacokinetics of beta-adrenoceptor blocking agents in man.

The structure and pharmacokinetics relationship of 14-beta-adrenoceptor antagonists was investigated in humans. Statistically significant linear and parabolic correlations were found to exist between standard and derived mean pharmacokinetic parameters and the apparent octanol/buffer (pH 7.4) partition coefficient of the compounds. The lipophilic/hydrophilic properties were the primary determinants for the pharmacokinetic behavior of the compounds. Most of the pharmacokinetic parameters were also significantly correlated with the plasma protein/plasma water partition coefficient for the compounds. When the values of the pharmacokinetic parameters of the individual compounds were predicted from the regressions on the apparent partition coefficients in octanol/buffer (pH 7.4) and in plasma protein/plasma water, the error was on average 60%.

Differences of sympathomimetic and anticholinergic action of OH-maprotiline and its R (-)-enantiomer.

1 C 49802 B-Ba and CGP 12103/A are the racemate and the R (-)-enantiomer respectively of the hydroxylated derivative of the tetracyclic antidepressant maprotiline, which differed in their ability to block noradrenaline-uptake and in their anticholinergic activity in animal models. 2 The sympathomimetic and anticholinergic activities of both substances were evaluated in eight healthy subjects and compared with the treatment with placebo and amitriptyline. 3 Heart rate, pupillary diameter, stimulated salivary flow rate and blood pressure were measured over a 15 h period keeping a very strict protocol. Plasma catecholamine levels were determined. 4 Saliva production was diminished following the administration of C 49802 B-Ba, CGP 12103/A and amitriptyline. 5 A moderate, but significant increase in heart rate and mean arterial blood pressure in the recumbent position was observed when C 49802 B-Ba was given. 6 The results in man are in agreement with the different activities found in animal experiments. 7 It can be concluded that the S (+)-enantiomer which the racemate contains is more active than the R (-)-enantiomer as to the anticholinergic and the sympathomimetic property.