Effect of pregnancy on emtricitabine pharmacokinetics.

OBJECTIVES: The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum. METHODS: The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6-12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography-mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC(0-24) ), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects. RESULTS: Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1-8.9) vs. 9.7 (8.6-10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6-28.3) vs. 20.6 (18.4-23.2) L/h (P = 0.025); 24 hour post dose concentration (C(24) ): 0.058 (0.037-0.063) vs. 0.085 (0.070-0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0-1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C(24) during pregnancy; however, the C(24) was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC(50) ) in all subjects. CONCLUSIONS: While we found higher emtricitabine CL/F and lower C(24) and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.

Nasal mucosal headache presenting as orofacial pain: a review of the literature and a case report.

Headaches are a significant component of many facial pain syndromes. These facial pain/headache syndromes often have various etiologies, including neurologic, vascular, musculoskeletal, or combinations of vascular/musculoskeletal origins. Referred rhinologic headache, however, can be overlooked as a cause of facial pain in the dental literature. We report a case of nasal mucosal headache that presented as facial pain and include a review of the literature.

A review of burning mouth syndrome.

Burning mouth syndrome is a complicated, poorly understood, predominantly oral condition that affects more than 1 million people in the United States. Women are particularly affected by the condition; they are diagnosed with symptoms seven times more frequently than males. Burning mouth syndrome is characterized by a burning, painful sensation of the oral mucosa that most commonly involves the anterior tongue. Many precipitating factors to burning mouth syndrome have been proposed, and treatment addressing these factors has had limited success. Patients with burning mouth syndrome are more likely to be evaluated by physicians, and therefore it is advantageous for the physician to be familiar with this oral condition. This paper reviews burning mouth syndrome, associated causative factors, and treatment strategies for the physician.

Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid.

Bile acid composition in fasting duodenal bile was assessed at entry and at 2 years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10-12 mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high-pressure liquid chromatography method that had been validated against gas chromatography. Percent composition in bile (mean +/- SD) for 98 patients at entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 +/- 18.6, 31.5 +/- 15.5, 8.0 +/- 9.3, 0.3 +/- 1.0, and 0.6 +/- 0.9. Values for CA were increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when compared with values in normal persons. Bile acid composition of the major bile acids did not change after 2 years on placebo medication. By contrast, in patients receiving UDCA for 2 years, bile became enriched with UDCA on average to 40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to 19.5%). No change in percent composition was observed for DCA and LCA. Percent composition at entry and changes in composition after 2 years on UDCA were similar in patients with varying severity of PBC. In patients whose bile was not enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the small amount of UDCA found in some of these specimens were conjugated to a greater extent with glycine (52%-64%) than with taurine (36%-48%). Treatment with UDCA caused the proportion of all endogenous bile acids conjugated with glycine to increase to 69% to 78%, while the proportion conjugated with taurine (22%-31%) fell (P <.05). Administered UDCA was also conjugated predominantly with glycine (87%).

An N-acyl glycyltaurine conjugate of deoxycholic acid in the biliary bile acids of the rabbit.

jj biliary bile acid composition of the adult and neonatal domestic rabbit, as well as that of the adult brush rabbit, was characterized. In adult domestic rabbits, the dominant bile acid present was deoxycholic acid (88% of total bile acids), a secondary bile acid formed by the bacterial 7-dehydroxylation of cholic acid. Although most of the bile acids present were conjugated with glycine, two exceptions were observed. About 3% of deoxycholic acid was conjugated, in N-acyl linkage, with glycyl-taurine. Chenodeoxycholic acid, which composed <1% of wile acids, was conjugated solely with taurine. The bile of neonatal rabbits contained a greater percentage of primary bile acids, and bile acids were conjugated to a much greater extent with taurine. The adult brush rabbit had a bile acid composition similar to that of the domestic rabbit, but about one-third of all bile acids were conjugated with taurine. In addition, lithocholic acid was present as its sulfated amidate, whereas in the domestic rabbit, lithocholic acid was conjugated solely with glycine. The biliary bile acid composition of rabbits appears to be unique both in terms of the predominant steroid moiety, as well as in the modes of conjugation.

Intraoral contact allergy: a literature review and case reports.

Signs and symptoms of contact allergic reactions affecting the oral mucosa may mimic other common oral disorders, making diagnosis difficult. Patients frequently seek multiple consultations and do not receive the correct diagnosis or effective management. As intraoral contact allergy may be more prevalent than previously believed, a review of this topic is warranted. This article emphasizes signs and symptoms that suggest intraoral contact allergy, and the authors discuss the allergens that most frequently affect the oral mucosa.

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis.

OBJECTIVE: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Lupus erythematosus: considerations for dentistry.

Lupus erythematosus, or LE, is a connective tissue disease that affects a number of organ systems. Patients with this condition can experience several other serious conditions--bleeding, infection, endocarditis, adrenal insufficiency and mucocutaneous disease--that can affect the provision of dental care. The authors describe considerations for managing dental treatment of patients with LE.

Fate of the predominant phospholipid component of DepoFoam drug delivery matrix after intrathecal administration of sustained-release encapsulated cytarabine in rats.

The distribution, metabolism, and excretion of dioleoylphosphatidylcholine (DOPC), the predominant phospholipid component of DepoFoam (DF) drug delivery matrix, was determined after lumbar intrathecal injection of double-radiolabeled ((14)CDOPC, (3)H-cytarabine) sustained-release encapsulated cytarabine (DF-cytarabine) in rats prepared with chronic spinal catheters. Radioactivity was quantitated in central nervous system (CNS) and peripheral tissues, cerebrospinal fluid (CSF), blood, urine, and feces at various time points up to 504 h. The distribution of (14)C radiolabel among lipid classes was also determined in selected body fluid samples. Both radiolabels distributed rapidly throughout the neuraxis after injection. Levels of both labels declined in a biphasic manner from CSF and plasma, with an initial rapid decline over the first 96 h, followed by a much slower rate of decline out to 504 h. Greater than 90% of the (3)H (drug) label was estimated to be excreted in urine. In contrast, the data suggest that most of the (14)C (phospholipid) label was expired as (14)CO(2); small percentages of the dose remained incorporated in CNS (7%) and peripheral tissues (8%) or were excreted in urine (6%). Characterization of lipidic (14)C in plasma confirmed metabolism of the parent lipid. The data confirm the sustained-release nature of the DF-cytarabine multivesicular liposomal preparation. Moreover, the results indicate that the DOPC lipid component enters standard catabolic path-ways after breakdown of the DF particles in the intrathecal space. Similar CSF and plasma kinetic profiles of drug and lipid radio-labels support the hypothesis that release of drug is related directly to breakdown of the lipid particles.

An improved method for the measurement of lidocaine and its metabolites in rat plasma.

An improved method is described for the quantitation of lidocaine and its dominant metabolites in rat plasma, 3-hydroxy-lidocaine glucuronide and 3-hydroxy-MEG-X glucuronide. Frozen plasma samples (100-200 microliters) were thawed and deproteinated by precipitation with acetonitrile, before the conversion of glucuronidates into their respective hydroxylated forms by acid hydrolysis. After extraction with solid-phase C18 cartridge chromatography, the metabolites and parent drug were analyzed by capillary gas chromatography-nitrogen phosphorus detection, without derivativization. A detection limit of 0.005 microgram/ml for lidocaine and nonglucuronidated metabolites and 0.01 microgram/ml for glucuronidated metabolites was achieved. The method offers significant improvements in sensitivity relative to existing techniques, which should be of specific benefit to studies in which sample volume is limited, such as those concerned with the pharmacokinetics of lidocaine metabolism in small-animal pain state models.

The pharmacokinetics of lignocaine in humans during a computer-controlled infusion.

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5 microg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V(1) = 7.44, V(2) =11.5 and V(3) = 97.71; Cl(1) = 0.585, Cl(2) = 2.23 and Cl(3) =1.64 l/min. Similarly calculated parameters using NONMEM were V(1) = 6.99, V(2) =12.2 and V(3) =1341; Cl(1) = 0.703, Cl(2) =1.24 and Cl(3) =1.49 l/min. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.

Dental considerations in asplenic patients.

The spleen plays an important role in the body's defense mechanism against microbial infections. However, trauma or diseases sometimes make removal of this important organ necessary, which predisposes patients to certain infections. This increased risk of infection and the underlying reason for the organ's removal both may affect the provision of dental care. This article reviews the structure and function of the spleen, conditions that may require its removal or cause its dysfunction, and provides considerations for dentists who care for asplenic patients.

Dental considerations for the patient with renal disease receiving hemodialysis.

An increasing number of Americans are living with end-stage renal disease. This disease has many implications for dentistry, in terms of oral manifestations and management of afflicted patients. The authors present pertinent information to help dentists treat patients who exhibit the oral and systemic manifestations of renal disease, from the onset of renal impairment through hemodialysis.

The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study.

Ursodeoxycholic acid (UDCA) and methotrexate (MTX) have both been proposed as treatments for patients with primary biliary cirrhosis (PBC). It has been suggested that a combination of the two drugs may offer advantages over either used separately. In this pilot study, we sought to evaluate the safety and efficacy of this combination for patients with PBC. Thirty-two patients with antimitochondrial antibody positive PBC were prospectively entered into a pilot study and received UDCA, 13 to 15 mg/kg/d, in conjunction with MTX, 0.25 mg/kg/wk, for a period of 2 years. The results of this treatment were compared with those obtained from 180 patients with PBC studied in a placebo-controlled trial of UDCA alone conducted during the same period. Patients in the pilot study and randomized study were comparable with regard to age, gender, and liver biochemistries. The UDCA/MTX-treated patients were of earlier histologic stage and had a lower mean Mayo risk score. During this period, seven patients in the UDCA/MTX group were withdrawn, four for pulmonary toxicity (two who required hospitalization), and one each with mouth ulcer, extreme fatigue, and hair loss. The use of UDCA/MTX was not associated with improvement in symptoms. In the patients receiving UDCA/MTX, biochemical changes were comparable to those of patients receiving UDCA alone but superior to those in the placebo group (P < .05). Histological changes were comparable in all groups at 2 years. Cessation of MTX while UDCA was continued led to no deterioration in liver biochemistries.(ABSTRACT TRUNCATED AT 250 WORDS)

Fecal bile acids, short-chain fatty acids, and bacteria after ileal pouch-anal anastomosis do not differ in patients with pouchitis.

Construction of an ileal reservoir changes the fecal bacterial flora and the fecal composition of bile acids and short-chain fatty acids. We examined the relationships between pouch inflammation (pouchitis) and pouch content, as assessed by analysis of fecal bacteria, bile acids, and short chain fatty acids. Four groups were studied: ileal pouch-anal anastomosis (IPAA) for ulcerative colitis with pouchitis (N = 10), IPAA without pouchitis (N =5), IPAA for familial adenomatous polyposis without pouchitis (N = 5); and Brooke ileostomy for ulcerative colitis, which served as controls (N = 5). Pouchitis was defined as > or = 7 points on an 18-point pouchitis disease activity index. Aerobic and anaerobic bacteria were quantitatively cultured. Total aqueous-phase bile acids were measured by thin-layer chromatography and an enzymatic 3 alpha-OH hydroxysteroid dehydrogenase method. Fecal short chain fatty acids were measured by gas liquid chromatography. All patients with an IPAA had higher ratios of anaerobes/aerobes and concentrations of anaerobic gram-negative rods than did patients with an ileostomy. There were no other differences between patient groups with respect to bacteria, aqueous-phase total bile acids, or fecal short-chain fatty acids. Fecal concentrations of bacteria, bile acids, and short-chain fatty acids were similar in patients with and without pouchitis, indicating that these factors can not be the sole cause of pouchitis.

Characterisation of patients with a complete biochemical response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) leads to biochemical and clinical improvement in many patients with primary biliary cirrhosis (PBC); although, the response is variable. This study compared UDCA treated patients with complete normalisation of biochemical functions to those without such improvement. Of the 65 patients receiving UDCA, 12 (19%) showed normalisation of liver biochemical functions at two years. The remaining 53 patients showed a less complete response. Mean (SD) alkaline phosphatase and total serum bilirubin values were significantly lower at entry in the patients whose liver biochemistry tests normalised (912 (732) U/l v 1417 (1021) U/l, p = 0.003, and 0.7 (12.1 (5.2) mumol/l v 38.9 (48.5) mumol/l, p = 0.0002, respectively), and percentage of UDCA in biliary bile acid was higher (56.3 (9.5)% v 38.3 (21.1)%, p = 0.03). Patients with biochemically and histologically less severe disease, and greater enrichment of biliary bile with UDCA, are more likely to respond favourably to the drug. The main objective of continued study will be to find out if normal liver biochemical functions can retard disease progression. The association of greater UDCA enrichment with complete biochemical responses suggests that higher doses of UDCA should be evaluated.

Bile acid metabolism and biliary secretion in patients receiving orthotopic liver transplants: differing effects of cyclosporine and FK 506.

Bile acid metabolism and biliary secretion were characterized in the first 2 wk after orthotopic liver transplantation in 15 patients receiving cyclosporine and in five patients receiving FK 506. Analyses were performed on hepatic bile obtained by T-tube drainage; values obtained were compared with literature values for bile samples obtained in patients who had undergone cholecystectomy. Biliary bile acid output, which is equivalent to bile acid biosynthesis from cholesterol, was low (mean +/- S.E.M.) and increased with time: day 1, 0.50 +/- 0.1 mmol/day; day 3, 0.8 +/- 0.1 mmol/day; and day 6, 1.6 +/- 0.5 mmol/day. Chenodeoxycholic acid biosynthesis, as percent of total bile acid biosynthesis, was abnormally low in patients receiving cyclosporine (16.2 +/- 1.1) but not in patients receiving FK 506 (38.2 +/- 4.8) (p < 0.005). Before the T-tube was clamped, the proportion of deoxycholic acid (a secondary bile acid formed by bacterial 7-dehydroxylation of cholic acid) was low in both groups: cyclosporine, 0.4 +/- 0.1; FK 506, 4.8 +/- 2.5 (p < 0.01). The mean concentration of bile acids in hepatic bile between days 4 and 11 did not differ significantly between groups: cyclosporine, 7.7 +/- 1.3 mmol/L; FK 506 4.3 +/- 0.7 mmol/L (mean +/- S.E.M.). (These values are similar to those reported for patients who have undergone cholecystectomy.) Bile acid-dependent bile flow, expressed as apparent choleretic activity (microliters of bile per micromole of bile acid output), was markedly elevated: in patients receiving cyclosporine the value was 129, and in patients receiving FK 506 the value was 220. (In patients who have undergone cholecystectomy, this value is less than 30).(ABSTRACT TRUNCATED AT 250 WORDS)

Cholylsarcosine, a new bile acid analogue: metabolism and effect on biliary secretion in humans.

BACKGROUND: Cholylsarcosine, the synthetic conjugate of cholic acid and sarcosine, is resistant to deconjugation-dehydroxylation during enterohepatic cycling in rodents and improves lipid absorption in a canine model of intestinal bile acid deficiency caused by distal intestinal resection. Experiments were performed to define its metabolism and effect on biliary secretion in humans. METHODS: The circulating bile acid pool was labeled with [14C]cholylsarcosine, and its turnover rate and biotransformation were determined by sampling bile daily. Cholylsarcosine (or cholyltaurine) was infused into the duodenum for 8 hours to define its effect on bile flow and biliary lipid secretion. RESULTS: Cholylsarcosine was lost rapidly from the enterohepatic circulation with a t1/2 of 0.5 days. The compound was not biotransformed by hepatic or bacterial enzymes. Cholylsarcosine had choleretic activity similar to that of cholyltaurine but induced more phospholipid and cholesterol secretion than cholyltaurine in four or five subjects. Infusion of cholylsarcosine (or cholyltaurine) at a rate averaging 0.6 mumol.min-1.kg-1 gave a biliary recovery of 0.2 mumol.min-1.kg-1; this value is the Tmax for active ileal transport of conjugated bile acids in humans. Laboratory tests for liver injury remained within normal limits. CONCLUSIONS: In humans, cholylsarcosine is not metabolized, is nontoxic, and has similar effects on biliary secretion as cholyltaurine. It appears safe to test in long-term studies the effect of cholylsarcosine on bile acid-deficiency states in humans.