Enumeration of the contaminating bacterial microbiota in unfermented pasteurized milks enriched with probiotic bacteria.

Pasteurized and unfermented milks supplemented with probiotic bacteria are appearing on the market. It then becomes a challenge to ascertain the undesirable contamination microbiota in the presence of a largely superior population of probiotic bacteria. A method to enumerate the contaminating microbial microbiota in such probiotic-enriched milks was developed. The probiotic cultures, Lactobacillus rhamnosus Lb-Immuni-T and Bifidobacterium animalis subsp. lactis BB-12(R), were added to a pasteurized unfermented milk to reach a minimum of 1 billion CFU per 250 mL portion, as ascertained by plating on de Man - Rogosa - Sharpe (MRS) agar in anaerobic conditions. No growth of B. animalis subsp. lactis BB-12 was noted on plate count agar (PCA) or Petrifilm plates, and the presence of this culture did not affect standard plate counts (SPC) of contaminating bacteria. However, L. rhamnosus formed colonies on PCA and Petrifilm plates. Attempts were thus made to inhibit the growth of the probiotic lactobacilli in PCA. The addition of 2% sodium phosphate (SP) or 5% glycerophosphate (GP) inhibited the growth of the lactobacilli in broths, but pin-point colonies of L. rhamnosus Lb-Immuni-T nevertheless appeared on PCA supplemented with phosphates. SPC could be obtained on PCA + 2% SP by only counting the large colonies, but this resulted in a significant (4.4 fold) underestimation of SPC values. On Petrifilm AC, at dilutions 0 to 2, all colonies were considered as being contaminants, while at dilutions 3 and 4, only large colonies were counted for SPC determinations. There was a direct correlation (R2 = 0.99) between SPC values with Petrifilm in uninoculated milks and those obtained on probiotic-enriched milks. The high correlation obtained over the 102 to 106 CFU/mL range of SPC values show that this Petrifilm method is appropriate to evaluate the microbiological quality of pasteurized milks enriched with L. rhamnosus Lb-Immuni-T and B. animalis subsp. lactis BB-12.

Enhancement of functional characteristics of mixed lactic culture producing nisin z and exopolysaccharides during continuous prefermentation of milk with immobilized cells.

Antagonistic phenomena between strains often occur in mixed cultures containing a bacteriocinogenic strain. A nisin Z producer (Lactococcus lactis ssp. lactis biovar. diacetylactis UL719) and 2 nisin-sensitive strains for acidification (Lactococcus lactis ssp. cremoris ATCC19257) and exopolysaccharide (EPS) production (Lactobacillus rhamnosus RW-9595M) were immobilized separately in gel beads and used to continuously preferment milk at different temperatures, with pH controlled at 6.0 by fresh milk addition. The process showed high volumetric productivity, with an increase from 8.0 to 12.5 L of prefermented milk per liter of reactor volume and hour as the temperature was increased from 27 to 35 degrees C. Lactococcus lactis ssp. lactis biovar. diacetylactis UL719 counts in prefermented and fermented (22-h batch fermentation) milks were stable during 3 wk of continuous fermentation (8.1 +/- 0.1 and 8.9 +/- 0.2 log cfu/mL, respectively). The L. lactis ssp. cremoris population (estimated with real-time quantitative PCR) decreased rapidly during the first week of continuous culture to approximately 4.5 log cfu/mL and remained constant afterward. Lactobacillus rhamnosus counts in prefermented and fermented milks significantly increased with prefermentation time, with no temperature effect. Nisin Z reached high titers in fermented milks (from 177 to 363 IU/mL), with EPS concentration in the range from 43 to 178 mg/L. Immobilization and continuous culture led to important physiological changes, with Lb. rhamnosus becoming much more tolerant to nisin Z, and Lb. rhamnosus and L. lactis ssp. lactis biovar. diacetylactis UL719 exhibiting large increases in milk acidification capacity. Our data showed that continuous milk prefermentation with immobilized cells can stimulate the acidification activity of low-acidifying strains and produce fermented milks with improved and controlled functional properties.

Media and process parameters affecting the growth, strain ratios and specific acidifying activities of a mixed lactic starter containing aroma-producing and probiotic strains.

AIMS: The effects of medium-composition and fermentation parameters on the properties of mixed mesophilic starters were studied. The starter was composed of Lactococcus lactis ssp. lactis (L. lactis), Lactococcus lactis ssp. cremoris (L. cremoris), Lactobacillus rhamnosus (Lact. rhamnosus) and Leuconostoc mesenteroides ssp. cremoris (Leuc. cremoris). METHODS AND RESULTS: The media used were reconstituted skim milk (RSM), and whey-based media with either citrate or phosphate buffers. The fermentation parameters were incubation temperature (22 degrees C or 32 degrees C), no pH control, and pH control in pH zones of either pH 6.0-5.8 or pH 6.0-5.2. The starter properties were strain ratio, specific acidifying activity (SAA), total population, residual carbohydrates and organic acids produced. The growth of L. lactis was favoured under pH control in whey-based media. High concentrations of Lact. rhamnosus were favoured in whey-based media prepared at 32 degrees C. The highest contents of Leuc. cremoris were obtained in starters prepared in RSM at 22 degrees C without pH control. Starters prepared under pH control gave the highest populations and made it possible for significantly lower inoculation rates (IR) to be used to carry out subsequent milk fermentations. However, the SAA of starters prepared under pH control were lower than the SAA of starters grown without any pH control. CONCLUSIONS: None of the conditions enabled the strain ratio at inoculation to be maintained. The data show that it is possible to prepare a mesophilic starter that has a significant probiotic Lact. rhamnosus content; this starter could be used in the preparation of probiotic-containing cheeses or in Leuc. cremoris for aroma production in fermented milks. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides data on what should be expected with respect to strain ratios and IR if cheesemakers decide to shift their aroma-producing starter production method from the traditional 'milk-based without pH control' method to whey-based media used with pH-zone control strategies.

Quantification by real-time PCR of Lactococcus lactis subsp. cremoris in milk fermented by a mixed culture.

During cheese making, interactions between different strains of lactic acid bacteria play an important role. However, few methods are available to specifically determine each bacterial population in mixed cultures, in particular for strains of the same species. The aim of this study was to develop a real-time PCR quantification method to monitor the population of Lactococcus cremoris ATCC 19257 in mixed culture with Lactobacillus rhamnosus RW-9595M and the bacteriocin-producing microorganism Lc. diacetylactis UL719. The specificity of the two primers 68FCa33 and 16SR308 used to amplify a 240-bp fragment of DNA from Lc. cremoris was demonstrated by conventional PCR. Using these primers for real-time PCR, the detection limit was 2 cfu/reaction or 200 cfu of Lc. cremoris ATCC 19257 per millilitre of mixed culture in milk. In pure culture batch fermentation, good correlation was obtained between real-time PCR and the conventional plating method for monitoring Lc. cremoris growth. In mixed culture batch fermentation, Lb. rhamnosus and Lc. cremoris decreased due to nisin Z production by Lc. diacetylactis. The decrease of the Lc. cremoris cell population detected by real-time PCR was not possible to observe by the plate count method in the presence of a Lc. diacetylactis population that was 1 log higher.

Effects of mixed starter composition on nisin Z production by lactococcus lactis subsp. lactis biovar. diacetylactis UL 719 during production and ripening of Gouda cheese.

A starter culture system that produced both acid and nisin at acceptable rates in milk for manufacture of Gouda cheese was developed using nisin Z-producing L. lactis subsp. lactis biovar. diacetylactis UL 719 (UL 719) and a commercial Flora Danica (FD) starter culture. Different compositions of mixed cultures (0, 0.2, 0.4, 0.6 or 0.8% UL 719 with 1.4% FD) were tested for acidification and nisin Z production in milk after 12 h incubation at 30 degrees C. The 0.6/1.4% combination, selected as the optimal mixture of starter cultures, acidified milk to a suitable pH and produced nisin Z at a high concentration of 512 IU/ml. With this optimal combination, FD numbers of citrate-fermenting and non-fermenting bacteria did not change compared with the control (1.4% FD). However, with 0.8% of L. lactis strain UL 719 and 1.4% of the FD starter culture, the numbers of citrate-fermenting and non-fermenting bacteria in fermented milk decreased compared with those obtained when milk was inoculated with 0.2, 0.4 or 0.6% of UL 719 added to 1.4% FD or control cultures (1.4% FD). Mixed starter culture ratios 0.6/1.4%, 0.4/1.4% and 0.5/1.4% (UL 719/FD) were used to manufacture nisin Z containing Gouda cheese which was ripened up to 45 weeks. The composition of control cheeses made with 1.4% FD, and nisin Z-containing Gouda cheeses were similar with respect to percent moisture, fat, salt and protein. During the ripening period, the cell counts observed were approximately two logs higher in cheese made with the 0.6/1.4% mixed starter culture than in control cheese. In experimental cheese produced with 0.6/1.4% (UL 719/FD) mixed starter culture, nisin activity increased from 256 IU/g at the end of manufacture to a maximum of 512 IU/g after 6 weeks of ripening; the levels then decreased to 128 and 32 IU/g after 27 and 45 weeks of ripening, respectively. In contrast, nisin Z was not detected in experimental cheeses made with 0.4/1.4% or 0.5/1.4% (UL 719/FD) mixed starters. Using an affinity purified anti-nisin polyclonal antibody, anti-rabbit gold-conjugate and transmission electron microscopy, nisin Z was found to be localized in the cheese matrix, in fat globules, in the casein phase and concentrated at the fat-casein interface. After 27 weeks of ripening, nisin Z was detected preferentially in the fat globules of the experimental cheese.

MR imaging of female pelvic malignancies.

This article reviews the most common gynecologic malignancies and their MR imaging features. The overall goal remains early disease detection and accurate staging to optimize treatment and thereby to reduce morbidity and mortality. MR imaging, when available, may play an important role in the accurate staging and evaluation of female pelvic malignancies and, thus, may become part of their routine investigation. In the authors' experience, MR imaging has proven useful in the preoperative evaluation of these malignancies. With ongoing research into imaging protocols designed to improve image quality and reduce examination time, the importance of MR imaging will continue to grow.

Infrarenal aortic stenosis: long-term clinical and hemodynamic results of percutaneous transluminal angioplasty.

PURPOSE: To evaluate the safety and long-term clinical and hemodynamic results of percutaneous transluminal angioplasty (PTA) of the infrarenal aorta. MATERIALS AND METHODS: During nearly 10 years, 102 patients with symptomatic infrarenal atherosclerotic aortic stenosis underwent PTA. Follow-up information was available in 92 patients (17 men, 75 women; mean age, 51.9 years). Stenosis involved the aortic bifurcation in 18 patients and only the infrarenal abdominal aorta in 74 patients. Technical success was defined as residual stenosis less than 50% or a pressure gradient less than 10 mm Hg after PTA. Clinical patency was defined as the absence or improvement of symptoms after PTA. Hemodynamic patency was defined as a normal Doppler waveform in the common femoral arteries, an ankle-brachial ratio greater than 0.95, or the absence of a thigh-brachial pressure gradient. RESULTS: Technical success was achieved in 78 patients after PTA. After 10 years, primary clinical and hemodynamic patency rates were 72% and 46%, respectively. After a mean follow-up of 51 months, 15 of the 22 symptomatic recurrences were due to aortic restenosis; 11 of these were treated with repeated PTA with or without stent placement, and three eventually required aortic surgery. No morbidity was encountered. CONCLUSION: Infrarenal aortic PTA proved to be safe and provided durable, long-term clinical improvement. In this group of relatively young patients, the clinical patency rate of PTA was equivalent to that of aortic surgery but with less morbidity.

Fenoldopam, a selective dopamine-1 receptor agonist, raises intraocular pressure in males with normal intraocular pressure.

Recent studies have suggested that intravenous infusion of fenoldopam, a selective dopamine-1 receptor agonist, elevates intraocular pressure (IOP) in man. This study evaluated the effect of intravenous fenoldopam on IOP, aqueous humor outflow facility and gonioscopy in 12 healthy human subjects. Three doses (0.2, 0.5 and 1.0 microg/kg/min) were infused for 120 minutes in a double masked, placebo controlled, four-way crossover design. IOP was measured every 20 minutes in the supine position and every 40 minutes while sitting during the drug and placebo infusions. Tonography and gonioscopy were performed at baseline and after 120 minutes of infusion. Compared to placebo, IOP increased by 3.5 mm Hg (32%) for the lowest dose, 5.8 mm Hg (46%) for the intermediate dose, and 6.9 mm Hg (55%) for the highest dose (p<0.05 for all three doses). IOP returned to baseline within 30 minutes of stopping the infusion. The outflow facility decreased from baseline by 26% after 120 minutes of infusion for all drug doses. In contrast, outflow facility increased from baseline by 11% during placebo infusion. Compared to placebo, the fenoldopam induced changes in outflow were statistically significant (p<0.05). There was no change in the gonioscopic appearance of the anterior chamber angle during the infusion. This study shows that systemic administration of a selective dopamine-1 receptor agonist causes a significant dose-dependent increase in IOP that can be explained in part by diminished outflow facility. These results support a role for the dopamine-1 receptor in the modulation of IOP in general and suggest modulation of aqueous humor outflow by dopaminergic receptors.

Effect of intravenous fenoldopam on intraocular pressure in ocular hypertension.

Intravenous fenoldopam, a selective dopamine-1 receptor agonist, was compared with placebo in this randomized, double-blind, two-period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open-angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 microgram/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P < 0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam-associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine-1 receptors play a role in the regulation of intraocular pressure.

Pharmacokinetics of testosterone in hypogonadal men after transdermal delivery: influence of dose.

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 +/- 10.5 years) were enrolled in an open-label, randomized, crossover study. Each application period comprised 4 days: a 2-day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patient's back. On day 4 of each period, serial blood samples were collected for determination of total and non-sex hormone binding globulin (non-SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration-time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non-SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.

Pharmacokinetics and absolute bioavailability of epristeride in healthy male subjects.

The objective of the current investigation was to describe the pharmacokinetics and absolute oral bioavailability of epristeride. Twelve healthy male subjects (mean (SD) age, 27 (6.2) years) received a single oral dose of 5 mg and an intravenous infusion of 4.5 mg over 30 min in a crossover fashion. Blood samples were obtained over 72h for the determination of epristeride plasma concentrations using a sensitive high-performance liquid chromatography assay. The lower limit of quantification was 5 ng mL-1. Pharmacokinetic analysis of the plasma concentration-time data was performed by both non-compartmental and compartmental methods. Absolute bioavailability was determined using dose-normalized AUC values following oral and intravenous administration. Epristeride plasma concentrations declined in a biexponential fashion with secondary peaks evident around 24 h in a majority of subjects following both routes of administration. Maximal plasma concentrations were typically achieved approximately 4 h after oral dosing. The mean apparent terminal elimination half-life estimates were similar following intravenous and oral administration and were 27.3 and 26.2 h, respectively. The mean plasma clearance and steady-state volume of distribution were 0.33 (0.09) mL min-1 kg-1 and 0.54 (0.17) L kg-1, respectively. The mean absolute bioavailability was 93% (95% CI: 84%, 104%). Following compartmental analysis of the intravenous data, the mean (SD) lambda 1 and lambda 2 half-life estimates were 2.74 (0.48) and 31.8 (19.5) h, respectively. The % AUC associated with the lambda 2 exponential phase was approximately 68%. This long half-life allows for once-daily dosing of epristeride.

Pharmacokinetics of famciclovir in subjects with chronic hepatic disease.

The pharmacokinetic profile of penciclovir was determined after a single 500-mg dose of its oral precursor, famciclovir, in 9 healthy volunteers and in 14 patients with chronic hepatic disease. Plasma and urine samples were analyzed for concentrations of penciclovir and 6-deoxy-penciclovir using a reverse-phase high-performance liquid chromatography (HPLC) method. Famciclovir was not quantifiable in patients with hepatic disease, and 6-deoxy-penciclovir was quantifiable in only a limited number of specimens. The extent of systemic availability of penciclovir, as measured by AUC0-infinity, was similar in patients with hepatic disease and in healthy subjects. In contrast, Cmax was significantly lower (average decrease of 43%) in subjects with hepatic disease relative to healthy normal subjects. Median Tmax for subjects with hepatic disease was significantly increased (by 0.75 hours) compared with subjects with normal liver function. These data suggest a decrease in the rate, but not the extent, of systemic availability of penciclovir in patients with hepatic disease. It should be unnecessary to modify the dose of famciclovir for subjects with compensated hepatic disease and normal renal function.

Comparative effects of nabumetone, sulindac, and indomethacin on urinary prostaglandin excretion and platelet function in volunteers.

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side-effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21-43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period-balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6-keto-PGF1 alpha, PGF2 alpha, thromboxane [TX] B2) and platelet function (collagen-induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2 alpha, but 6-keto-PGF1 alpha and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6-keto-PGF1 alpha and TXB2 excretion rates. Reduced excretion of PGF2 alpha was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6-keto-PGF1 alpha excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2 alpha excretion and between the NAB and SUL regimens for PGE2, PGF2 alpha, 6-keto-PGF alpha 1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6-keto-PGF1 alpha, suggests that NAB possesses renal sparing properties.

Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment.

OBJECTIVE: To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment. METHODS: Twenty-seven subjects were enrolled in an open-label parallel-group study. Eighteen patients had renal impairment (average age [ +/- SD], 49 +/- 12 years), and nine subjects were healthy volunteers (average age, 28 +/- 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CLCR): mild impairment (CLCR, 60 to 80 ml/min/1.73 m2), moderate impairment (CLCR, 30 to 59 ml/min/1.73 m2) and severe impairment (CLCR, 5 to 29 ml/min/1.73 m2). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reverse-phase HPLC. Plasma data were analyzed with use of model-independent methods. RESULTS: In subjects with normal renal function (CLCR > 80), the mean maximum plasma concentrations of penciclovir was 2.83 micrograms/ml (range, 1.30 to 3.82 micrograms/ml) and the mean time to reach maximum concentration was 0.89 hours (range, 1/2 to 1 1/2 hours). The mean apparent terminal elimination half-life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CLCR and between renal clearance and CLCR. Mean area under the plasma concentration-time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function. CONCLUSION: Consideration should be given to modification of the dosing schedule of famciclovir from the usual 8-hour interval to a 12-hour interval for patients with moderate renal impairment (CLCR 30 to 59 ml/min/1.73 m2) or a 24-hour interval for patients with severe renal impairment (CLCR < 30 ml/min/1.73 m2).

Fenoldopam reverses cyclosporine-induced renal vasoconstriction in kidney transplant recipients.

Cyclosporine causes renal vasoconstriction and reduced renal blood flow that may contribute to chronic nephrotoxicity. This effect has not been consistently reversed by available pharmacologic agents. The efficacy of orally administered fenoldopam, a dopamine-1 (DA-1) agonist with renal vasodilator properties, was evaluated in six patients whose condition was stable 3 to 6 months following renal transplantation. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate (PAH) clearances, respectively, at baseline, after the acute oral administration of 100 mg of fenoldopam, and following 3 weeks of chronic oral fenoldopam therapy (100 mg thrice daily). Mean ERPF increased from 3.15 +/- 0.17 mL/s/1.73 m2 (189 +/- 10 mL/min/1.73 m2) at baseline to 3.48 +/- 0.17 mL/s/1.73 m2 (209 +/- 10 mL/min/1.73 m2) 4 hours after acute administration of fenoldopam (P = 0.04). Urine flow rate and fractional excretion of sodium also increased after acute administration, but not significantly. Mean systolic (SBP) and diastolic blood pressure (DBP) decreased maximally by 18 and 6 mm Hg, respectively, and mean pulse rate increased maximally by 8 bpm between 75 and 90 minutes after both acute and chronic administration. GFR was unchanged following both acute and chronic administration. The increase in ERPF was not maintained to the end of the dosing interval during chronic administration, probably due to the short half-life of fenoldopam. However, the renal vasodilatory response was still observed 3 to 4 hours after readministration of the drug following 3 weeks of oral dosing. Thus, fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of probenecid effect on nonrenal excretion of ceftriaxone in anephric patients.

Probenecid has been shown to decrease renal and biliary excretion of organic acids. In a randomized crossover study, the effect of coadministered probenecid on nonrenal excretion of ceftriaxone was studied in six functionally anephric patients in whom ceftriaxone is eliminated exclusively by nonrenal or presumably by biliary excretion. Each patient received 0.5 g IV ceftriaxone without and with probenecid (0.5 g at 10 and 2 hours prior to ceftriaxone and 0.5 g q12h X 3 doses post ceftriaxone). Serial blood samples were collected over 48 hours and plasma analyzed for ceftriaxone by high performance liquid chromatography (HPLC). Pharmacokinetic analysis was based on a model-independent approach. Probenecid did not significantly affect the disposition of ceftriaxone in this study, thus suggesting that nonrenal excretion of ceftriaxone is not inhibited by probenecid.

Sugar Utilization and Acid Production by Free and Entrapped Cells of Streptococcus salivarius subsp. thermophilus, Lactobacillus delbrueckii subsp. bulgaricus, and Lactococcus lactis subsp. lactis in a Whey Permeate Medium.

Cells of Streptococcus salivarius subsp. thermophilus and Lactococcus lactis subsp. lactis entrapped in k-carrageenan-locust bean gum gel performed similarly to free cells in the conversion of lactose to lactic acid. Bead diameter influenced the fermentation rate. Cells entrapped in smaller beads (0.5 to 1.0 mm) showed higher release rates, higher lactose, glucose, and formic acid utilization, higher galactose accumulation, and higher lactic acid production than did cells entrapped in larger beads (1.0 to 2.0 mm). Values for smaller beads were comparable with those for free cells. Immobilization affected the fermentation rate of lactic acid bacteria, especially Lactobacillus delbrueckii subsp. bulgaricus. Entrapped cells of L. delbrueckii subsp. bulgaricus demonstrated a lower lactic acid production than did free cells in batch fermentation. The kinetics of the production of formic and pyruvic acids by L. lactis subsp. lactis and S. salivarius subsp. thermophilus are presented.

Effect of chronic renal failure on oxaprozin multiple-dose pharmacokinetics.

The effects of renal disease on the steady-state kinetics of oxaprozin were assessed in eight patients on hemodialysis with normal serum albumin levels and eight normal subjects who received six doses. A larger clearance and volume of distribution at steady state for total and unbound oxaprozin occurred in the patients on hemodialysis. The elimination half-lives were not different. The mean total AUC, peak concentration, average steady-state plasma concentration, and trough concentration for total and unbound oxaprozin were decreased in the patients on hemodialysis. These differences are consistent with impaired absorption of oxaprozin in patients on hemodialysis. The higher dose-averaged unbound fraction of oxaprozin in plasma in patients on hemodialysis may be caused by endogenous binding inhibitors. Because clearance was not reduced in patients on hemodialysis, the dose of oxaprozin may not need to be reduced when albumin levels are normal.

Effect of renal impairment on disposition of pentopril and its active metabolite.

Disposition of pentopril was studied in 15 male volunteers with varying renal functions. Mild to moderate compromise in renal function did not demonstrate any appreciable changes in plasma concentration of pentopril, the prodrug ester of the active angiotensin-converting enzyme (ACE) inhibitor CGS 13934. This is consistent with the known elimination pattern for pentopril, which is eliminated primarily by hydrolysis to the active inhibitor. In contrast, the plasma concentration of the active ACE inhibitor was sensitive to moderate changes in renal function. Because of the reciprocal relationship of AUC and clearance, AUC did not change to any appreciable extent until creatinine clearance (CLCR) dropped to about 50 ml/min. Below 50 ml/min of CLCR, AUC and half-life increased sharply with reduced kidney function. Because of the significant contribution of the renal secretion process to total renal elimination of both pentopril and the active metabolite, prediction of renal clearance from CLCR was poor at relatively normal kidney function (CLCR greater than 80 ml/min). However, renal secretory clearances for both pentopril and metabolite were well correlated to p-aminohippuric acid clearance. In patients with moderately compromised renal function (glomerular filtration rate less than 40 ml/min), tubular secretion rate of creatinine approaches its glomerular filtration rate and hence CLCR could be used as a predictor of renal clearance and other disposition parameters. Plasma ACE activity also demonstrated prolonged inhibition with decreased renal function. Based on the prolonged blockade of plasma ACE activity, some correction in dose or dosing interval is anticipated in patients with moderately compromised renal function (CLCR less than 50 ml/min).