Liver transplantation in an adolescent with acute liver failure from acute lymphoblastic leukemia.

The most common identifiable causes of acute liver failure in pediatric patients are infection, drug toxicity, metabolic disease, and autoimmune processes. In many cases, the etiology of acute liver failure cannot be determined. Acute leukemia is an extremely rare cause of acute liver failure, and liver transplantation has traditionally been contraindicated in this setting. We report a case of acute liver failure in a previously healthy 15-yr-old male from pre-B-cell acute lymphoblastic leukemia. He underwent liver transplantation before the diagnosis was established, and has subsequently received chemotherapy for pre-B-cell acute lymphoblastic leukemia. He is currently alive 31 months post-transplantation. The published literature describing acute lymphoblastic leukemia as a cause of acute liver failure is reviewed.

Quantitative light-induced fluorescence to measure enamel remineralization in vitro.

UNLABELLED: The aim of this study was to compare the ability of quantitative light-induced fluorescence (QLF) and surface microhardness (SMH) to measure the remineralization of enamel subsurface lesions, using a pH-cycling model including treatment with 0-ppm, 550-ppm or 1,100-ppm sodium fluoride (NaF) dentifrices. METHODS: Subsurface lesions were created in human enamel specimens (n = 36) and exposed to a remineralization pH-cycling model for 14 days. The pH-cycling model was performed in an automated system where specimens were subjected to a demineralizing solution for 20 min and treatment for 1 min and were then remineralized for 7 h 39 min, 3 times daily. The treatments consisted of 3 NaF, silica-containing dentifrices (0 ppm F; 550 ppm F; 1,100 ppm F). The outcome variables were: change from baseline in surface hardness and percentage change from baseline in fluorescence. An ANCOVA explored differences between different treatment groups (at the p < 0.05 level). Associations between QLF and SMH were evaluated using Spearman's correlation coefficient. RESULTS: The percentage SMH changes were 14.9 ± 2.1%, 56.6 ± 9.6% and 103.9 ± 14.6% for the 0-, 550- and 1,100-ppm F dentifrices, respectively. The percentage fluorescence changes were 15.6 ± 7.1%, 59.8 ± 11.9% and 85 ± 13.2%, respectively. The differences between all pairwise comparisons were statistically significant for both methods (p = 0.001). QLF correlated with SMH (r = 0.67). CONCLUSIONS: Both the SMH and QLF methods demonstrated a significant F dose response for toothpaste in this in vitro remineralization model, and both methods were able to distinguish treatments with different F levels.

Evaluation of a dentifrice containing 8% arginine, calcium carbonate, and sodium monofluorophosphate to prevent enamel loss after erosive challenges using an intra-oral erosion model.

OBJECTIVE: The objective of this study was to assess the ability of a dentifrice containing 8% arginine and calcium carbonate (Pro-Argin' Technology), and 1450 ppm fluoride as sodium monofluorophosphate (MFP) to prevent enamel loss from an erosive acid challenge in comparison to a silica-based dentifrice with 1450 ppm fluoride as MFP using an intra-oral erosion model. METHODS: The intra-oral clinical study used a double blind, two-treatment, crossover design. A palatal retainer was used to expose the enamel specimens to the oral environment during the five-day treatment period. The retainer was designed to house three partially demineralized bovine enamel samples. The study population was composed of 24 adults, ages 18 to 70 years. The study consisted of two treatment periods, with a washout period lasting seven (+/- three) days preceding each treatment phase. A silica-based dentifrice without fluoride was used during the washout period. The Test Dentifrice used in this study contained 8% arginine and calcium carbonate (Pro-Argin Technology), and 1450 ppm fluoride as sodium monofluorophosphate (MFP). The Control Dentifrice was silica-based and contained 1450 ppm fluoride as MFP. The treatment period lasted five days, during which the panelists wore the retainer 24 hours a day (except during meals and the ex vivo acid challenges) and brushed with their assigned product while wearing the retainer. The panelists brushed once in the morning and once in the evening each day for one minute, followed by a one-minute swish with the slurry and a rinse with 15 ml of water. The panelists brushed only their teeth and not the specimens directly. There were four ex vivo challenges with 1% citric acid dispersed throughout the day: two in the morning, one in the afternoon, and one in the evening. Mineral loss was monitored by a quantitative light fluorescence (QLF) technique. RESULTS: Twenty-three of 24 subjects successfully completed the study. The one subject who did not complete the study did so for reasons unrelated to the study or products used. The average percent mineral loss for the Test Dentifrice and Control Dentifrice was 9.74 +/- 13.23 and 18.36 +/- 14.14, respectively. The statistical analysis showed that the observed product differences were statistically significant (p < 0.001). CONCLUSION: The Test Dentifrice with 8% arginine, calcium carbonate, and 1450 ppm fluoride as MFP provided significantly better protection against erosive challenges in comparison to the Control Dentifrice with 1450 ppm fluoride as MFP.

Evaluation of a dentifrice containing 8% arginine, calcium carbonate, and sodium monofluorophosphate to repair acid-softened enamel using an intra-oral remineralization model.

OBJECTIVE: An intra-oral remineralization study was conducted to compare the ability of a dentifrice containing 8% arginine and calcium carbonate (Pro-Argin Technology), and 1450 ppm fluoride as sodium monofluorophosphate (MFP) to remineralize acid-softened bovine enamel specimens compared to a silica-based dentifrice with 1450 ppm fluoride as MFP. METHODS: The intra-oral clinical study employed a double blind, two-treatment, crossover design, and used an upper palatal retainer to expose the enamel specimens to the oral environment during product use and periods of remineralization. The retainer was designed to house three partially demineralized bovine enamel samples. The study population was comprised of 30 adults, ages 18 to 70 years. The study consisted of two treatment phases with a washout period lasting seven (+/- three) days preceding each treatment phase. A silica-based dentifrice without fluoride was used during the washout period. The Test Dentifrice used in this study contained 8% arginine, calcium carbonate, and 1450 ppm fluoride as sodium monofluorophosphate (MFP). The Control Dentifrice was silica-based and contained 1450 ppm fluoride as MFP. The treatment period consisted of a three-day lead-in period with the assigned product. The panelists brushed two times per day during the three-day lead-in period with the assigned product. On the fourth day, the panelists began brushing with the assigned product with the retainer in their mouth. The panelists brushed for one minute, followed by a one-minute swish with the slurry and a rinse with 15 ml of water in the morning, in the afternoon, and night with the retainer in the mouth. The panelists brushed only their teeth and not the specimens directly. Changes in mineral content before and after treatment were measured using a Knoop microhardness tester. RESULTS: The results of the study showed that percent remineralization values for the Test Dentifrice and Control Dentifrice were 14.99% and 8.66%, respectively. A statistical analysis showed that the Test Dentifrice was statistically significantly more effective at remineralizing acid-softened enamel in comparison to the Control Dentifrice (p < 0.05). CONCLUSION: This study demonstrated that the Test Dentifrice with 8% arginine, calcium carbonate, and 1450 ppm fluoride as MFP is highly effective treatment for promoting remineralization of enamel that has been softened by an erosive challenge.

Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation.

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5-5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49-year-old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition-related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12-15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus-associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.

Use of vascularized posterior rectus sheath allograft in pediatric multivisceral transplantation--report of two cases.

Restoring abdominal wall cover and contour in children undergoing bowel and multivisceral transplantation is often challenging due to discrepancy in size between donor and recipient, poor musculature related to birth defects and loss of abdominal wall integrity from multiple surgeries. A recent innovation is the use of vascularized posterior rectus sheath to enable closure of abdomen. We describe the application of this technique in two pediatric multivisceral transplant recipients--one to buttress a lax abdominal wall in a 22-month-old child with megacystis microcolon intestinal hypoperistalsis syndrome and another to accommodate transplanted viscera in a 10-month child with short bowel secondary to gastoschisis and loss of domain. This is the first successful report of this procedure with long-term survival. The procedure has potential application to facilitate difficult abdominal closure in both adults and pediatric liver and multivisceral transplantation.

Identification of spermine as an inhibitor of erythropoiesis in patients with chronic renal failure.

Fetal mouse liver and normal human bone marrow cell cultures were used for studies on the inhibition of erythroid colony formation (CFU-E) by sera from anemic patients with end-stage renal failure and the polyamine spermine. Sera from each of eight predialysis uremic anemic patients with end-stage renal failure produced a significant (P < 0.001) inhibition of erythroid colony formation in the fetal mouse liver cell cultures when compared to sera from normal human volunteers. In vivo or in vitro dialysis of the uremic sera with a 3,500-dalton exclusion limit membrane removed the inhibitor from uremic sera. The uremic serum dialysate provided by the membrane fractionation was significantly inhibitory in the erythroid cell cultures. When this dialysate was applied to gel filtration chromatography (Bio-Gel P-2) the inhibitor was found to be in the same molecular weight range as [(14)C]spermine. The polyamine spermine produced a dose-related inhibition of erythroid colony formation (CFU-E) in fetal mouse liver and normal human bone marrow cultures. Thus, the following evidence is provided that the in vitro inhibitor of erythropoiesis found in chronic renal failure patients' sera is identical with the polyamine spermine: (a) the inhibitor and radiolabeled spermine appeared in identical Bio-Gel P-2 effluent fractions; (b) when spermine was added to normal human sera at concentrations reported in sera of uremic patients, and studied in both the fetal mouse liver cell culture and normal human bone marrow cultures, a dose-related inhibition of erythroid colony (CFU-E) formation was noted; and (c) the inhibitory effects of crude uremic serum, uremic serum dialysate, and fractions of uremic serum dialysate from a Bio-Gel column, on erythroid colony formation were completely abolished by the addition of a specific rabbit antiserum to spermine.

Glass transition temperature prediction of polymers through the mass-per-flexible-bond principle.

A semi-empirical method based on the mass-per-flexible-bond (M/f) principle was used to quantitatively explain the large range of glass transition temperatures (T(g)) observed in a library of 132 L-tyrosine derived homo, co- and terpolymers containing different functional groups. Polymer class specific behavior was observed in T(g) vs. M/f plots, and explained in terms of different densities, steric hindrances and intermolecular interactions of chemically distinct polymers. The method was found to be useful in the prediction of polymer T(g). The predictive accuracy was found to range from 6.4 to 3.7 K, depending on polymer class. This level of accuracy compares favorably with (more complicated) methods used in the literature. The proposed method can also be used for structure prediction of polymers to match a target T(g) value, by keeping the thermal behavior of a terpolymer constant while independently choosing its chemistry. Both applications of the method are likely to have broad applications in polymer and (bio)material science.

Role for heparin-binding growth factors in glucose-induced vascular dysfunction.

Vascular hyperpermeability and excessive neovascularization are hallmarks of early and late vascular endothelial cell dysfunction induced by diabetes. Vascular endothelial growth factor (VEGF) appears to be an important mediator for these early and late vascular changes. We reported previously, using skin chambers mounted on backs of SD rats, that neutralizing antibodies directed against VEGF blocked vascular permeability and blood flow changes induced by elevated tissue glucose and sorbitol levels in a dosage-dependent manner. We report in this study, using the same skin chamber model and neutralizing antibodies directed against basic fibroblast growth factor (FGF-2), that another member of the heparin-binding growth factor family also mediates glucose- and sorbitol-induced vascular permeability and blood flow increases. In addition, we show that 1) TBC1635, a novel heparin-binding growth factor antagonist, blocks the vascular hyperpermeability and blood flow increases induced by elevated tissue levels of glucose and sorbitol and by topical application of VEGF and FGF-2 to granulation tissue in skin chambers, and 2) suramin, a commercially available growth factor antagonist, blocks glucose-induced vascular dysfunction. These results suggest an early role for heparin-binding growth factors in the vascular dysfunction caused by excessive glucose metabolism, possibly via the sorbitol pathway.

Urinary excretion of 6-hydroxychlorzoxazone as an index of CYP2E1 activity.

OBJECTIVE: To determine whether the urinary excretion of 6-hydroxychlorzoxazone is an index of CYP2E1 activity in vivo. METHODS: Male volunteers (n = 27; age range, 17 to 36 years) who were abstinent from alcohol were studied. Chlorzoxazone, 500 mg, was given orally and plasma was collected at 31/2, 41/2, 51/2, and 61/2 hours after dosing. Urine was collected for 8 hours. Ten volunteers participated in full kinetic studies to define the absorption phase and plasma area under the concentration-time curve of chlorzoxazone and the urinary kinetics of the 6-hydroxy metabolite. Chlorzoxazone and the 6-hydroxy metabolite were measured by high-performance liquid chromatography. CYP2E1 activity was expressed as a hydroxylation index (HI = mmole oral chlorzoxazone dose/mmole 6-hydroxychlorzoxazone in 8-hour urine). RESULTS: There was a significant positive correlation between plasma elimination rate constant for chlorzoxazone (Ke) and urinary excretion of the metabolite (n = 27, r = 0.42, p < 0.03) and a significant negative correlation between plasma Ke and HI (n = 27, r = -0.41, p < 0.04). The mean absorption rate constant for chlorzoxazone of 3.11 +/- 4.67 hr-1 was fivefold greater than the plasma Ke of 0.57 +/- 0.17 hr-1 for the full kinetic studies. The formation clearance of the 6-hydroxy metabolite was negative between plasma Ke of the parent compound and disposition rate constant for urinary excretion of the 6-hydroxy metabolite (n = 15, r = 0.85, p < 0.0001). CONCLUSIONS: The urinary excretion of 6-hydroxychlorzoxazone is limited by formation rate and may be useful as an in vivo probe of CYP2E1 activity.

Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus.

Zidovudine is metabolized to an inactive 5'-glucuronide and has a short plasma half-life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficiency virus was undertaken to determine if coadministration of valproic acid which, like zidovudine, is metabolized by glucuronidation, would alter zidovudine disposition. Under steady-state conditions for both drugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with valproic acid. The mean 5'-glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudine recovered in urine increased by more than twofold. There was no significant increase in the plasma half-life of zidovudine. The effects of valproic acid on zidovudine glucuronidation were related to plasma valproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single-dose and steady-state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus-seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half-life (t1/2) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long-term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10- to 14-fold higher than the corresponding single-dose concentrations. The terminal t1/2 (washout) after 16 weeks greatly exceeded the t1/2 observed after a single oral dose (151 versus 29.6 hours). Ribavirin-induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.

Purification and characterization of a tyrosine aminotransferase from Crithidia fasciculata.

Tyrosine aminotransferase (TAT, EC 2.6.1.5) from the kinetoplastid, Crithidia fasciculata, was purified over 2000 fold to electrophoretic homogeneity. The native form of the enzyme had a molecular weight of approximately 100,000, whereas under denaturing conditions it produced two polypeptides of approximately 50,000 and 48,000, respectively. Absence of a reaction with the periodic acid-Schiff stain suggested that the crithidial enzyme was not a glycoprotein. It was relatively stable and remained active over a wide range of pH and temperature. It exhibited a broad substrate specificity and was able to utilize L-tyrosine, L-tryptophan, and L-phenylalanine as amino donors. Antiserum produced against partially purified crithidial tyrosine aminotransferase failed to inhibit the enzymatic activity. The same antiserum cross-reacted with a soluble extract from Trypanosoma brucei gambiense, but not with that from normal mouse liver, confirming evolutionary conservatism between the two protozoa.

Isolation and characterization of a cysteine proteinase from Fasciola hepatica adult worms.

Adult Fasciola hepatica worms contain multiple proteinases capable of degrading hemoglobin, immunoglobulins and collagen. Here we report the isolation and biochemical characterization of a cysteine proteinase from acidic extracts of these worms. The enzyme was purified to homogeneity by cation exchange and molecular sieve high-performance liquid chromatography. It eluted at a native molecular weight of approximately 14,500 and migrated as a single band at approximately 14,500 Da upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Activity was assessed by employing synthetic peptide substrates, such as carbobenzoxy-phenylalanyl-arginyl-7-amino-4-trifluoro-methylcoumarin, commonly used to assay other cysteine proteinases. The proteinase was maximally active at pH 6.0, with 50% or more of the activity detected between pH 4.5 and 7.5. Inhibition of activity at pH 5.5 was seen only with compounds known to inhibit cysteine proteinases. No effect was seen with inhibitors of aspartic, serine, or metalloproteinases. The purified enzyme was stable at acidic pH at 4 degrees C, 25 degrees C, -20 degrees C, and in 1 M urea.

Effect of sulfur substitution for the noncarbonyl oxygen in hemicholinium-3 and acetyl-seco-hemicholinium-3. Synthesis, biological activity, and structure-toxicity relationships.

As a continuation of our efforts to develop and study inhibitors which act presynaptically on neuromuscular function, sulfur analogues of hemicholinium-3 (HC-3, 1) and acetyl-seco-hemicholinium-3 (AcHC-3, 3) were prepared. In each case sulfur is substituted for the noncarbonyl oxygen in HC-3 (1) and AcHC-3 (3). As expected on the basis of conformational differences between acetylcholine and acetylthiocholine both of the thio analogues are produced in the seco form and do not cyclize spontaneously or when subjected to aqueous, acidic conditions up to 100 degrees C. Both compounds are stable in aqueous pH 7.4 solutions at 37 degrees C and in slightly acidic D2O solutions for more than 24 h. While thio-seco-hemicholinium 3 (11) is stable in the presence of acetylcholinesterase and butyrylcholinesterase in H2O at pH 7.4, acetylthio-seco-hemicholinium-3 (12) reacts within seconds to form the hemiacetal form of thiohemicholinium-3 (16). Mouse toxicity studies (LD50) indicate that while 12 is approximately as toxic as HC-3 (1) and AcHC-3 (3), 11 is 226 times less toxic. As in the studies with 1 and 3, mice were protected from 11 by choline and slightly by neostigmine. It is of interest, however, that almost equal and intermediate protection against 12 was afforded by choline and neostigmine. Structure-toxicity relationships of 1,3,11, 12, and 16 are discussed.

Synthesis and structure-toxicity relationships of three new stable analogues of acetyl-seco-hemicholinium-3.

In order to develop and study inhibitors of neuromuscular function which act presynaptically, three stable analogues of acetyl-seco-hemicholinum-3 (AcHC-3,2) were prepared. These analogues have 2-ethoxyethyltrimethylammonium, 4-oxopentyltrimethylammonium, and n-pentyltrimethylammonium moieties substituted for the 2-acetylethyltrimethylammonium (acetylcholine) moieties of AcHC-3 (2) to form the ether 2, ketone 4, and alkane 5 analoggues of AcHC-3 (2). Although AcHC-3 (2) has been shown to undergo deesterification rapidly in basic solutions and slowly at pH 7.4, it has been found to be stable in H2O or D2O under slightly acidic conditions. All of the analogues are stable for extended time under both slightly acidic conditions and at pH 7.4 in H2O or D3O. It has been found that 2 reacts with acetylcholinesterase and butyrylcholinesterase within seconds in H2O at pH7.4. However, deesterification of 2 with subsequent cyclization to the hemiacetal form of hemicholinium-3 (HC-3, 1) is prevented at pH 7.4, possibly by an irreversible binding of 2 to the enzyme. The analogues 3-5, however, do not react under identical conditions. Mouse toxicity studies (LD50) indicate that 2 is approximately as toxic as HC-3 (1), whereas 3, 4, and 5 are 14.2, 23.8, and 43.1 times less toxic, respectively. The toxic effects of 3-5, like 1 and 2, are antagonized by choline but not by neostigmine in mice. Structure-activity relationships of 2-5 are discussed.

The high molecular weight fibroblast growth factor-2 isoforms (21,000 mol. wt and 23,000 mol. wt) mediate neurotrophic activity on rat embryonic mesencephalic dopaminergic neurons in vitro.

Basic fibroblast growth factor is expressed in different isoforms which display tissue and species specificity and are differentially regulated during development and after experimental interventions. The differential regulation of the fibroblast growth factor-2 isoforms may indicate specific activities and functions of these molecules. The characterization of fibroblast growth factor-2 effects, however, is almost exclusively based on studies including the 18,000 mol. wt isoform. It is not yet known whether the high molecular weight fibroblast growth factor-2 isoforms (21,000 mol. wt, 23,000 mol. wt) exert similar or distinct activities in the nervous system. In the present study, we investigated the effects of the high molecular weight isoforms on dissociated rat mesencephalic dopaminergic neurons. For this purpose, recombinant fibroblast growth factor-2 isoforms, prepared in a histidine expression system, were administered on dopaminergic neurons in vitro, and Schwann cells over-expressing the high molecular weight isoforms were co-cultured with dopaminergic neurons. This is the first demonstration to show that the high molecular weight isoforms mediate a neurotrophic activity. Exogenous high molecular weight fibroblast growth factor-2 isoforms stimulated the survival of embryonic mesencephalic dopaminergic neurons and protected them from 6-hydroxydopamine neurotoxicity. In addition, co-culture of dopaminergic neurons with high molecular weight fibroblast growth factor-2 over-expressing Schwann cells revealed an increased survival and neurite formation of the mesencephalic dopaminergic neurons. These results suggest that the high molecular weight fibroblast growth factor-2 isoforms may serve as a new tool for the treatment of Parkinson's disease.

High-pressure liquid chromatography/electrochemical detection method for monitoring MDA and MDMA in whole blood and other biological tissues.

The drug Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) is one of several hallucinogenic amphetamine derivatives reported to be serotonergic neurotoxins. The following is a description of a new high-pressure liquid chromatographic (HPLC) analytical method for the analysis of MDMA, 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDE) from whole blood. Upon separation of MDMA, MDA and MDE by HPLC, quantitation is achieved by use of electrochemical detection. Retention times for MDA, MDMA, and MDE are 6.5, 9.2, and 10.3 min, respectively, allowing for a complete chromatographic run every 15 min. The sensitivity of the method is 1 ng/ml which allows for measurement of MDA, MDMA, or MDE in microsamples of whole blood. The volume of blood required is very small (200 microliters); therefore, there is minimal blood loss in repeated blood sampling from small animals. Assay linearity was demonstrated from 1 ng/ml to at least 1 microgram/ml. The coefficients of variation for both intra-assay and inter-assay comparisons were less than 9%. Other HPLC methods have been previously described for the analysis of amphetamine derivatives, but this new method offers greater sensitivity, rapid turn-around time and ease of use.

Myelography with metrizamide: effect of contrast removal on side effects.

Moderately severe side effects, such as prolonged headache, nausea, vomiting, or psychoneurologic symptoms, were noted in 27 (32%) of 84 patients in whom the contrast medium was not removed. Conversely, among 73 patients from whom 20-25 ml of cerebrospinal fluid with the contrast medium was removed, only 10 (14%) experienced adverse effects, a statistically significant reduction. Although new contrast agents, such as iohexol and iopamidol, are reportedly less toxic than metrizamide, the contrast-removal technique described here may be indicated when large amounts of any contrast medium are used.

Valproic acid increases cerebrospinal fluid zidovudine levels in a patient with AIDS.

Valproic acid is an anticonvulsant drug known to inhibit the glucuronidation of zidovudine (AZT) in human liver microsomes. Zidovudine is metabolized by glucuronidation to the inactive 5'-glucuronide with a short plasma half-life (1.0 +/- 0.2 hour). This case presentation confirms that valproic acid inhibits glucuronidation in vivo, and this is the first documented observation of increased cerebrospinal fluid levels of zidovudine because of an interaction with valproic acid in a patient with acquired immune deficiency syndrome (AIDS). The peak plasma AZT level for the control period was 119 ng/mL, which increased almost 3-fold to 344 ng/mL with valproic acid (1.5 g/day). The plasma AZT trough was 47 ng/mL, which also increased almost 3-fold to 124 ng/mL with valproic acid. The molar ratio of plasma 5'-glucuronide/AZT at the peak was reduced from 1.77 (control) to 1.07 with valproic acid. The 5'-glucuronide/AZT ratio at the trough was reduced markedly from 5.0 (control) to 0.93 with valproic acid, suggesting in vivo inhibition of glucuronidation. Cerebrospinal AZT levels, drawn 30 minutes after peak plasma levels, increased from 27 ng/mL for the control to 47 ng/mL with valproic acid, which paralleled the change in peak plasma concentrations. This interaction with valproic acid may contribute to higher AZT levels in the brains of patients with human immunodeficiency virus-related (HIV) encephalopathy.