The potential of salivary biomarkers of nutritional status and dietary intake: A Systematic Review.

OBJECTIVES: To explore whether nutritional salivary biomarkers could be used to aid nutritional status assessment and/or support traditional dietary assessment methods for patients. DATA AND SOURCES: Searches were performed using four electronic databases; MEDLINE, EMBASE, Scopus and Web of Science. Trial registers (i.e. Cochrane), grey literature and reference lists were searched. STUDY SELECTION: Studies which measured nutritional salivary biomarkers related to nutritional status and/or dietary intake outcome were included. No restrictions on participants' age, study design, publication date, setting or health status. Animal studies, non-English language studies, commentaries, and conference abstracts were excluded. RESULTS: Study titles and abstracts were screened (n = 7982), full-texts assessed (n = 176) and 85 studies were included in a narrative synthesis. The most promising salivary biomarkers for nutritional status included: glucose, where saliva and serum levels were positively correlated in those with type 2 diabetes (T2D), higher salivary calcium levels in post-menopausal women in general and specifically those with lower bone mineral density (BMD), and salivary vitamin D to assess vitamin D status in healthy volunteers. Higher salivary total antioxidant capacity (TAC), nitrate/nitrite and fluoride were observed with increased antioxidant, nitrate/nitrite and fluoride dietary intake, respectively. A meta-analysis found significantly higher mean salivary glucose (n = 12) in T2D compared with healthy controls, but there was substantial heterogeneity (I2=94%) and evidence of publication bias. CONCLUSIONS: The most promising salivary biomarkers identified in this systematic review were, glucose, vitamin D, calcium, TAC, nitrate/nitrite and fluoride. However, this was based on a small number of studies of varying quality, with many lacking a salivary assay performance assessment. CLINICAL SIGNIFICANCE: At present, nutritional salivary biomarkers cannot be used alone to assess nutritional status or dietary intake. Further research into the most promising nutritional salivary biomarkers is required.

Sympathetic nerve damage as a potential cause of lymphoedema after axillary dissection for breast cancer.

BACKGROUND: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor. METHODS: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet. RESULTS: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema. CONCLUSION: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery.

Is the MIC useful in deciding to treat endocarditis surgically?

The infecting pathogen and its susceptibility to antibiotics is used to suggest prognosis in endocarditis. A case study was performed in a tertiary referral cardiology centre to assess the contribution of the measurement of minimum inhibitory concentration (MIC) to the decision to treat endocarditis surgically. The records were examined of 125 patients admitted between 1981 and 1999 in whom the minimum inhibitory concentration for the pathogen had been measured. The measures of outcome were mortality at time of hospital discharge and at 6 months, surgical referral and cure by medical treatment. Endocarditis caused by Staphylococcus aureus with a raised MIC of flucloxacillin (methicillin) was associated with higher mortality even if glycopeptides were used in treatment (< or = 35 mg/l 0/7 versus MIC 1-2 mg/l 4/13, P = 0.01). Elevated MICs of flucloxacillin in S. aureus infection or of gentamicin in streptococcal disease were associated with surgical intervention. There were no significant differences between bacterial pathogens in mortality, surgical referral or cure by medical treatment. The measurement of MIC appears prognostically important in deciding the surgical management of endocarditis.

Mortality from infective endocarditis: clinical predictors of outcome.

OBJECTIVE: To identify clinical markers available within the first 48 hours of admission that are associated with poor outcome in infective endocarditis. DESIGNS: Retrospective cohort study. SETTING: Teaching hospital. PATIENTS: 208 of 220 patients with infective endocarditis. METHODS: Consecutive patients with infective endocarditis presenting between 1981 and 1999 to a tertiary centre were studied. Clinical, echocardiographic, and haematological data recorded within 48 hours of admission were obtained. Data were analysed using logistic regression models. MAIN OUTCOMES MEASURES: Mortality at discharge and at six months. RESULTS: Data were obtained for 93% of patients who were eligible for inclusion. 194 (93%) were positive for Duke criteria. Mean age was 52 (1.2) years, and 138 (66%) were men. 82 (39%) were transferred from other hospitals. 181 (87%) were blood culture positive, and 47 (23%) infections were Staphylococcus aureus. The infection was located on aortic (n = 85, 41%), mitral (n = 77, 37%), tricuspid (n = 18, 9%), and multiple valves (n = 20, 10%). 67 (32%) had prosthetic valve endocarditis. 48% of the cohort were managed with antibiotics alone. Mortality at discharge was 18% and at six months 27%. Duration of illness before admission, age, sex, valve infected, infecting organism, and left ventricular function were not predictors of adverse mortality. However, abnormal white cell count, serum albumin concentration, serum creatinine concentration, or cardiac rhythm, the presence of two major Duke criteria, or visible vegetation conferred a poor prognosis. CONCLUSIONS: Conventional prognostic factors in this study did not appear to predict outcome early during hospital admission. However, simple clinical indices, which are readily available, are reliable, cheap, and potentially powerful predictors of poor outcome.

Investigating the relationship between beta-blocker and antidepressant use through linkage of the administrative databases of Saskatchewan Health.

The main objectives of this research were to confirm previous reports of an increased risk of antidepressant use subsequent to propranolol therapy, and to determine whether this higher relative risk (RR) is indicative of depressive symptoms as a side-effect of the drug's use. 'New' users of beta-blockers, other antihypertensives or diuretics in two separate years were identified from records of Saskatchewan Health. Incidence of concurrent antidepressants prescribing was determined in the year after initiating therapy with a cohort drug. Medical claims were examined to identify physician services and diagnoses associated with cohort drug and antidepressant prescriptions. Risk of concurrent antidepressant use in new propanolol users aged 20-39 years was approximately double that of new diuretic users [RR 2.2 (1.5-3.3) in 1984 and 2.0 (1.1-3.5) in 1990/91]. When cases with a diagnosis of migraine headache were excluded, the risk of concurrent propranolol/antidepressant use was age- and sex-dependent, but not consistent for the two study years. It was concluded that although the risk of concurrent antidepressant use was greater in younger propranolol users, the risk cannot be solely attributed to depressive side-effects of the drug. The purposes of this paper were to present the methods employed in linking the databases of Saskatchewan Health, describe the results of the analysis, and to highlight the methodologic problems that arose.

Prospective, randomized, controlled evaluation of a gentamicin loading dose in neonates.

A prospective, randomized, controlled evaluation comparing a 4-mg/kg loading dose (LD) of gentamicin to the standard regimen of 2.5 mg/kg every 12, 18 or 24 h was conducted in critically ill neonates. The objective of the study was to compare the time required to achieve a therapeutic peak serum concentration (i.e. the number of dosing intervals) and to compare the number of serum concentrations outside the therapeutic range as an indicator of potential toxicity between the treatment groups. Eighteen of 26 patients, 5 of 13 in the control group and 13 of 13 in the LD group (p = 0.012) achieved an initial peak concentration of > or = 5 micrograms/ml following the first gentamicin infusion. There were no significant differences between the control and LD group in the number of potentially toxic serum concentrations. When patients were subdivided according to gestational age (GA), patients of < or = 34 weeks had significantly lower initial peak concentrations. A LD of 4 mg/kg in neonates, particularly those of < or = 34 weeks GA, produced a therapeutic peak concentration following the initial dose. There is a minimal risk of attaining serum concentrations commonly associated with toxicity providing the dosage interval is adjusted based on serum creatinine determinations. Based on this study, infants of > 34 weeks GA generally achieve therapeutic peak concentrations after the first dose with conventional dosing; however, in younger infants an appropriate LD is required to reach therapeutic concentrations early in therapy.

Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal.

The effect of probenecid on the pharmacokinetics of diflunisal and its glucuronide and sulphate conjugates was studied in 8 healthy volunteers. Diflunisal 250 mg b.d. was administered p.o. for 15 days and its steady state pharmacokinetics was evaluated on Day 16 after the last dose (control phase). Probenecid 500 mg b.d. was co-administered throughout the entire study period in the treatment phase of the study. The steady state plasma concentration of diflunisal was significantly higher during the probenecid treatment phase as compared to the control phase (104.0 vs. 63.1 micrograms.ml-1). This was the result of a significant decrease in the plasma clearance of diflunisal from 5.8 (control) to 3.4 ml.min-1 (probenecid co-administration). The metabolite formation clearances of both glucuronides were significantly decreased by probenecid, -45% and -54% for the phenolic and acyl glucuronide, respectively. The metabolite formation clearance of the sulphate conjugate was not affected by probenecid coadministration. Steady state plasma concentrations of the sulphate and glucuronide conjugates of diflunisal were 2.5- to 3.1-fold higher during probenecid co-administration, due to a significant reduction in the renal clearance of the three diflunisal conjugates. Probenecid also reduced the plasma protein binding of diflunisal, but only to a minor extent; the unbound plasma fraction of diflunisal at steady state averaged between 5 and 30% higher during probenecid co-administration.

Non-steroidal anti-inflammatory drugs: restrictive or non-restrictive hepatic clearance?

Based on their hepatic extraction ratio and unbound fraction in plasma or blood, drugs can be categorized as being restrictively or non-restrictively eliminated. The general perception is that drugs with very small plasma clearances and extensive plasma protein binding, such as warfarin, are eliminated restrictively. However, based on literature data for 18 non-steroidal anti-inflammatory drugs (NSAIDs) with low plasma clearances (< 60 ml/min), we have shown that most of these low-extraction compounds are non-restrictively eliminated, i.e. their hepatic extraction ratio exceeds their unbound fraction in plasma. For 4 NSAIDs considered in this survey, i.e. phenylbutazone and the oxicams piroxicam, isoxicam and tenoxicam, the hepatic extraction ratio is smaller than their unbound fraction in plasma, and their hepatic elimination, therefore, is restrictive. Our conclusion that most low-clearance NSAIDs are non-restrictively extracted is based on a number of realistic assumptions concerning their pharmacokinetic characteristics: 1. their elimination is exclusively hepatic, 2. bioavailability of their oral dosage form is complete, and 3. they do not undergo extensive reversible biotransformation or enterohepatic circulation.

Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis.

The pharmacokinetics of diflunisal, a salicylate derivative that undergoes phenolic and acyl glucuronidation as well as sulphate conjugation, has been studied after a single oral dose (250 mg) in patients with cirrhosis (n = 5) and in healthy controls (n = 5). The plasma clearance of total (bound + unbound) diflunisal was 10.2 ml.min-1 in the control subjects and it was not affected by cirrhosis (10.9 ml.min-1). The plasma protein binding of diflunisal was significantly reduced in cirrhosis; the percentage of unbound diflunisal in plasma was 0.089 in the controls and 0.147 in the patients with cirrhosis. Plasma clearance of unbound diflunisal was significantly impaired in cirrhosis: 11.5 l.min-1 in control subjects vs 7.41.min-1 in cirrhotics. In cirrhotic patients, the unbound partial clearances to the phenolic and acyl glucuronides were both significantly reduced, by approximately 38%. The unbound partial clearance to the sulphate conjugate was not significantly affected by cirrhosis. The results show that both the phenolic and acyl glucuronidation pathways of diflunisal are equally susceptible to the effects of liver cirrhosis.

Increased serum sulfate concentrations in man due to environmental factors: effects on acetaminophen metabolism.

Serum sulfate concentrations were determined in volunteers consuming municipal drinking water with varying sulfate contents--77 ppm in Saskatoon and 1157 ppm in Rosetown. The serum sulfate concentrations were subsequently monitored after the administration of single or multiple-dosing regimens of acetaminophen, which undergoes sulfoconjugation, to determine whether sulfate concentrations in serum changed. Average serum sulfate concentrations were 0.35 mmol/L (Saskatoon) and 0.50 mmol/L (Rosetown). Saskatoon volunteers had a significant fall in serum sulfate concentrations during the multiple-dosing regimen. This was not seen in the Rosetown participants. The rates of urinary excretion and renal clearance of sulfate were significantly higher in the Rosetown volunteers. Except for the multiple-dosing t1/2 levels, the Cmax, tmax, AUC and Cl/f of acetaminophen were not significantly different within or between the 2 groups. The excretion of sulfate and glucuronide conjugates of acetaminophen was not significantly different between the 2 groups, but there was a difference within each group with respect to single and multiple-doses. Excretion of the sulfate conjugate fell significantly in the Saskatoon volunteers during the multiple-dose portion of the study, whereas the percentage excreted as the glucuronide increased. The consumption of 15-fold greater sulfate levels in drinking water increased the sulfate concentration in serum. However, this increased concentration did not significantly alter the sulfoconjugation of acetaminophen.

Simple method for the determination of inorganic sulfate in human serum and urine using single-column ion chromatography.

A single-column ion chromatographic assay with conductivity detection was developed to determine inorganic sulfate concentrations in human plasma and urine samples. Plasma samples were ultrafiltered to remove proteins. Plasma ultrafiltrate and urine samples were diluted prior to injection onto the anion-exchange column. The described method is simple, fast, sensitive and reproducible and was used to study the effect of subchronic administration of acetaminophen on the plasma concentrations and urinary excretion of inorganic sulfate in healthy volunteers.

Increased prescribing of antidepressants subsequent to beta-blocker therapy.

Using records of the Saskatchewan Prescription Drug Plan, we determined the incidence of antidepressant use (a marker for depressive symptoms) in patients who received beta-blockers or other treatments for chronic diseases (diuretics, antihypertensives, and hypoglycemics) during 1984, but not in the previous 6 months. Antidepressants initiated within 12 months after the study drug were counted. Of the 3218 new beta-blocker users, 6.4% received concurrent prescriptions (ie, within 34 days) for an antidepressant and beta-blocker. Only 2.8% of the reference group (no study drug use) received an antidepressant. A greater proportion of patients prescribed propranolol (9.5%) received an antidepressant than those prescribed other "lipophilic" (3.9%) or "hydrophilic" (2.5%) beta-blockers. Incidence ratios for propranolol revealed the overall risk antidepressant use was 4.8 (95% confidence interval [CI], 4.1 to 5.5) times that of the reference group and 2.1 (95% CI, 1.7 to 2.5) times that of all other study drug users. For propranolol, relative risk of antidepressant use (drug/reference group) varied with age and was greatest in the 20- to 39-year-old group (17.2; 95% CI, 13.7 to 21.5).

Circadian rhythm of serum sulfate levels in man and acetaminophen pharmacokinetics.

The circadian variation of serum inorganic sulfate levels was studied in healthy volunteers. The effect of subchronic acetaminophen administration (650 mg q.i.d. for 4 days) on serum inorganic sulfate levels was investigated and the possible role of fluctuating serum inorganic sulfate levels on the pharmacokinetics of acetaminophen was evaluated. During a 24 h cycle, serum inorganic sulfate levels were lowest in the morning (11.00 h) and typically increased in the afternoon to reach a maximum in the early evening (19.00 h). Average 24 h serum concentrations were 360 microM and the difference between minimum and maximum levels was on average 25.8%. Subchronic administration of acetaminophen (650 mg q.i.d. for 4 days) significantly reduced serum inorganic sulfate levels to a 24 h average of 253 microM. The circadian rhythm, however, was not affected and the difference between minimum (12.00 h) and maximum (18.50 h) serum concentrations was 31.3%. Subchronic acetaminophen administration lead to a significant decrease in the renal excretion (-51%) and renal clearance (-33%) of inorganic sulfate. No significant differences were found in the disposition kinetics of acetaminophen and its glucuronide and sulfate conjugates during two consecutive dosing intervals (08.00-14.00 h, 14.00-20.00 h) on Day 4 of the acetaminophen regimen.

Single and multiple dose pharmacokinetics of enteric coated ketoprofen: effect of cimetidine.

The effect of cimetidine on the single and multiple dose pharmacokinetics of enteric coated ketoprofen was studied in 12 healthy volunteers. Each subject completed two 8-day study treatment periods: either ketoprofen alone (100 mg p.o. twice daily), or co-administered with cimetidine (600 mg twice daily). tlag, Cmax, tmax, t1/2, and k for ketoprofen were not significantly different between single and multiple dose administration. AUC of ketoprofen was slightly but significantly larger following multiple (21.2 micrograms.h.ml-1) as compared to single dose administration (19.0 micrograms.h.ml-1). As a result, plasma clearance of ketoprofen was slightly but significantly reduced following multiple dose administration (80.6 ml/min vs 89.3 ml/min). Cimetidine had no effect on the single or multiple dose pharmacokinetics of enteric coated ketoprofen. Total 12-h urinary recovery of ketoprofen (mostly in the form of ketoprofen glucuronide) was 83.5% of the dose following single dose administration and was significantly greater following multiple dose administration (93.1%). Again cimetidine co-administration had no effect on the single and multiple dose urinary recovery. The results of this study show that cimetidine is not affecting the oral pharmacokinetics of enteric coated ketoprofen.

The effect of age on piroxicam disposition in rheumatoid arthritis.

The disposition of piroxicam in 23 patients with rheumatoid arthritis (9 males, 14 females, aged 27-79) was studied over 6 weeks using the standard oral dose of 20 mg daily. Clinical status was monitored using standard methods. The mean piroxicam steady state plasma concentration (Css) averaged 9.2 +/- 4.4 micrograms/ml, the majority of which was highly protein bound (1.4 +/- 0.5% unbound). Total plasma clearance (CL/F) of piroxicam was 1.85 +/- 0.81 ml/min and the half life (t1/2) was 53.0 +/- 24.2 h. There was wide intersubject variability in the kinetics of piroxicam and its major metabolite 5'-hydroxypiroxicam. Piroxicam CL/F, t1/2 and Css were modestly correlated with patient age. Clinical effects did not appear to be related to piroxicam plasma levels.

Plasma protein binding of drugs in the elderly.

Binding to plasma proteins can affect the pharmacokinetics and pharmacodynamics of drugs. Age is one of many factors which can affect plasma protein binding of drugs. Unfortunately, very few generalities can be drawn from the studies of the effect of age on protein binding. Whether age has an effect on protein binding is dependent not only on the drug, but also on the manner in which the study is conducted. Several studies involve patients with various disease states making assessment of the effect of age alone on protein binding difficult. Results of different studies on the same drug do not always agree--in one case finding no change in protein binding with age and in another, a significant increase or decrease in protein binding. Most drugs which exhibit increased binding (decreased free fraction) in elderly subjects are basic and tend to have a greater affinity for alpha 1-acid glycoprotein than for albumin. The list of drugs exhibiting decreased binding (increased free fraction) in the elderly is longer and includes both acidic and basic drugs. The impact of changes in protein binding with age is dependent on the magnitude of the change, on the pharmacokinetic characteristics of the drug and on its therapeutic index. Some changes, although statistically significant, are not likely to be of importance clinically. From the studies reviewed, the free fraction is changed by greater than 50% in the elderly for only a few drugs, e.g. acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate and zimeldine.

Cerebrospinal fluid and plasma beta-endorphin concentrations in prolonged infant apnea (near-miss sudden infant death syndrome).

Elaboration of beta-endorphins (beta-ED) is implicated in the modulation of respiratory control in infants. Therefore, beta-ED concentrations were measured in paired samples of CSF and plasma in three groups of infants. Group 1 and group 3 were used as controls. Group 2 infants suffered prolonged apnea of infancy (near-miss sudden infant death syndrome) and were successfully resuscitated. Age and weight (mean +/- SEM) in groups 1, 2 and 3 were 8.5 +/- 3 months and 7.2 +/- 1.4 kg, 3.8 +/- 0.7 months and 5.2 +/- 0.6 kg, and 3.4 +/- 0.9 months and 3.4 +/- 0.7 kg, respectively. CSF beta-ED concentrations were found to be significantly elevated in group 2, 67.8 +/- 4.7 pg/ml, when compared to group 1, 29.8 +/- 3.1 pg/ml, and group 3, 46.5 +/- 7.2 pg/ml (p less than 0.01). No correlation was observed with plasma and CSF concentrations in all three groups. beta-ED may play a role in the pathophysiology of prolonged infant apnea (near-miss sudden infant death syndrome).

The effect of acetaminophen administration on its disposition and body stores of sulphate.

This investigation was designed to investigate the effects of ingestion of multiple therapeutic doses of acetaminophen on the disposition of the drug and on the cosubstrate, sulfate. Nine healthy volunteers and nine outpatients receiving acetaminophen for chronic pain were involved in the study. Volunteers were given a single 650 mg oral dose of acetaminophen. One week later they were given 650 mg of acetaminophen every six hours for five doses. Patients were maintained on their normal treatment and dosage schedules (600 mg every 3 to 8 h) for the study. In healthy volunteers the half-life of acetaminophen after single and multiple dosing was not significantly different. However, the fraction of acetaminophen recovered in the urine as the sulfate conjugate was less and the glucuronide conjugate greater after multiple dosing than after a single of the drug. There was no difference in the percentage recovered as the parent compound between single and multiple dosing. Serum sulfate levels fluctuated over the 6-h period following administration of single and multiple doses of acetaminophen to volunteers. The mean serum sulfate concentration was less after administration of five sequential 650 mg doses of acetaminophen than after a single dose. The renal clearance of inorganic sulfate showed a corresponding decrease. Unexpectedly, patients on chronic acetaminophen therapy exhibited elevated serum sulfate levels (levels higher than the maximum sulfate concentration seen in volunteers).

In vitro interaction of aminoglycosides with beta-lactam penicillins.

The aminoglycosides are used clinically in combination with beta-lactam antibiotics. The combined use, however, produces an interaction and inactivation of the antibiotics. A study was designed to investigate the kinetics of the interaction in vitro. Four concentrations of aminoglycosides (5 to 20 micrograms of gentamicin and tobramycin per ml) and penicillins (100 to 600 micrograms of carbenicillin and ticarcillin per ml) were incubated in plasma (3 days, 37 degrees C). Samples taken at 12-h intervals were analyzed for both aminoglycosides (radioimmunoassay) and penicillin (high-pressure liquid chromatography). In controls, degradation of all four antibiotics were by first-order reactions. In incubation mixtures of two antibiotics, the rate of loss of the aminoglycosides was greater than that in the controls, whereas the rate of loss of penicillins was not significantly increased. The loss of penicillins in incubation mixtures still appeared to be by first-order reactions. However, semilogarithmic plots of aminoglycoside concentrations were curvilinear, suggesting a second-order reaction. Aminoglycoside concentrations in incubation mixtures were fitted by computer to a model incorporating a second-order interaction between aminoglycosides and penicillins and the first-order loss of penicillin from the mixture. The interaction rate constant averaged 2.2 X 10(-4) (micrograms/ml h)-1 for interaction of both carbenicillin and ticarcillin with gentamicin and 1.6 X 10(-4) (micrograms/ml h)-1 for interaction of the penicillins with tobramycin. The effect of the interaction in vivo was examined by computer simulation using the kinetic parameters determined in vitro.