Urinary Enzymes and Protein Patterns as Indicators of Injury to Different Regions of the Kidney

Urinary Enzymes and Protein Patterns as Indicators of Injuryto Different Regions of the Kidney. STONARD, M. D., GORE, C.W., OLIVER, G. J. A., AND SMITH, I. K. (1987). Fundam. Appl.Toxicol. 9, 339–351. Acute experimental models of renaldamage to the proximal tubular, glomerular, and papillary regionsof the rat were produced by administration of hexachloro 1:3-butadiene(HCBD), puromycin aminonucleoside (PAN), and 2-bromoethylamine(BEA), respectively. Several routine indicators of nephrotoxicity,the enzymes alkaline phosphatase and N-acetyl-ß-glucosaminidase,and the molecular weight pattern of protein excretion were determinedon urine samples. Tubular damage produced by HCBD or BEA wasdiscriminated both quantitatively and qualitatively from glomerulardamage produced by PAN. The latter was characterized by a pronouncedincrease in protein excretion, especially proteins with molecularweight >40,000 Da. In contrast, protein excretion in tubulardamage was raised only slightly and characterized by excretionof proteins of a wide range of molecular weights. Proximal tubulardamage caused by HCBD and papillary damage caused by BEA weredistinguished both by conventional urinalysis (volume and specificgravity) and by measurement of the two urinary enzymes. Alkalinephosphatase and glucose were markedly and transiently elevatedin proximal tubular damage and N-acetyl-ß-glucosaminidaseshowed a sustained elevation in papillary damage. It is concludedthat both selective urinary enzymes and the molecular weightpattern of urinary proteins can be used to provide diagnosticinformation about the possible site of renal damage.     

Subcutaneously administered recombinant human β-interferon in the treatment of chronic hepatitis B virus infection

Background: Treatment of chronic replicative hepatitis B virus (HBV) infection is aimed at stopping viral replication and preventing the development of chronic liver disease. β-Interferon treatment has been less well studied than α-interferon. Methods: The efficacy and tolerability of a 6-month course of subcutaneously administered human recombinant β-interferon (rINF-β_ser) was studied and the results of a low-dose regime compared with a high-dose regime. Twenty patients (17 men and three women), aged 24–54 years, with chronic hepatitis B virus infection (all hepatitis B surface antigen-positive with detectable HBV-DNA in their sera for at least 3 months prior to therapy) were randomized into two treatment groups of 10 patients each. The low-dose group received 6×10⁶ U/dose and the high-dose group received 30×10⁶ U/dose, both groups receiving their respective doses three times a week initially for 1 month and continuing for a total of 6 months. Results: The treatment was well tolerated in both groups. None of the patients required dosage reduction or cessation of treatment because of side-effects. HBV-DNA decreased in all patients during treatment, demonstrating the anti-viral efficacy of rINF-β_ser, and was undetectable in 20 and 40% of patients receiving low-dose and high-dose regimes, respectively, at the end of 6 months treatment (P=N.S.). One year after completion of treatment, HBV-DNA was undetectable in 50 and 30% of patients in the low-dose and high-dose groups, respectively (P=N.S.). However, only one patient achieved seroconversion with loss of the hepatitis B surface antigen and appearance of an anti-hepatitis B ‘e’ antigen at the end of 18 months. Conclusion: This study shows that subcutaneously administered rINF-β_ser is well tolerated, but the optimal dose and duration of treatment still needs to be defined by further studies.     

LOCAL RADIOTHERAPY FOR PEDAL MANIFESTATIONS OF HLA-B27-RELATED ARTHROPATHY

Four males with characteristic foot manifestations of HLA-B27-relatedarthropathy are reported. The severity of this problem and itsrecalcitrance to standard therapies led to the use of localradiotherapy. The beneficial outcome and minimal short-termside effects of this treatment are discussed in relation toprevious experience with radiotherapy in ankylosing spondylitis. KEY WORDS: HLA-B27, Radiotherapy, Spondyloarthropathy, Enthesopathy     

THE IMPACT OF ALCOHOL ON THE ACUTE HOSPITAL SERVICE: PATIENT PRESENTATION, ADMISSION AND THE PERCEPTION OF ALCOHOL USE IN SUCH GROUPS

Patients presenting to an Emergency Department were assessedby a standard questionnaire and clinical examination as to thecontribution that alcohol made to their presentation and theperception of their alcohol use. Patients under the influenceof alcohol are more than twice as likely not to fill in simplequestionnaires and not to perceive their alcohol consumptionas different from non-drinking fellows. Emergency Departmentsare not the optimal site for the education and motivation ofdrinking patients to alter their future habits.     

Acute, Distribution, and Subchronic Toxicological Studies of Succinate Tartrates

The estimated single-dose oral toxicity (50% lethality) of succinatetartrates (ST) was 2–3 g/kg in rats. ST produced minimalto moderate dermal irritation but no evidence of systemic toxicityin a standard acute percutaneous toxicity test in rabbits. STwas not an eye irritant in a standard rabbit low-volume eyeirritation test ST was not genotoxic in a series of six genotoxicitytests. A 14-day oral gavage study in rats at a dose range of0.05–1.0 g ST/kg/day produced only gastric irritation.The no-observed-effect level (NOEL) for gastric irritation was0.1 g/kg for males and 0.05 g/kg for females. A 28-day percutaneoustoxicity study in rabbits produced minimal to moderate dermalirritation and no adverse systemic effects at a high dose of450 mg ST/kg/day. Single-dose absorption, distribution, andelimination (ADE) studies in male rats showed that 10–15%of an oral dose and 1–3% of a dermal dose were absorbed.Approximately 98% of the orally administered ST was eliminatedas ¹⁴C in urine, feces, or expired CO₂ after 72 hr. Approximately80% of the dermally absorbed ¹⁴C dose was eliminated in urine,feces, or expired CO₂ after 72 hr. In conclusion, no adverseeffects were noted in acute toxicity, genotoxicity, or subchronictoxicity studies conducted with ST.     

Developmental Toxicity of Dichloroacetonitrile: A By-Product of Drinking Water Disinfection

Developmental Toxicity of Dichloroacetonitrile: A By-productof Drinking Water Disinfection. SMITH, M. K., RANDALL, J. L.,STOBER, J. A., AND READ, E. J. (1989). Fundam. Appl. Toxicoi.12, 765–772. Dichloroacetonitrile (DCAN), a by-productof drinking water disinfection formed by reactlon of chlorinewith background organic materials, was evaluated for its developmentaleffects in pregnant Long-Evans rats. Animals were dosed by oralintubation on Gestation Days 6=18 (plug = 0) with 0, 5, 15,25, or 45 mg/kg/day. Tricaprylin was used as a vehicle. Thehighest dose tested (45 mg/kg) was lethal in 9% of the damsand caused resorption of the entire litter in 60% of the survivors.Embryolethality averaged 6% per litter at the low dose and 80%at the high dose and was statistically significant at 25 and45 mg/kg/day. The incidence of soft tissue malformations wasdose related and was statistically significant at doses toxicto the dam (45 mg/kg). These anomalies were principally in thecardiovascular (interventricular septal defect, levocardia,and abnormalities of the major vessels) and urogenital (hydronephrosis,rudimentary bladder and kidney, fused ureters, pelvic hernia,cryptorchidism) systems The frequency of skeletal malformations(fused and cemcal ribs) was also, dose related and significantlyincreased at 45 mg/kg. The no-observed-adverse-effect dose fortoxicity in pregnant Long-Evans rats was established by statisticalanalysis to be 15 mg/kg/day.     

Bropirimine-Induced Embryolethality after Oral Administration to the Pregnant Rat

Oral bropirimine (an immunomodulator shown to induce interferon)was administered to timed-pregnant Sprague-Dawley rats in fiveexperiments utilizing several different dosing schedules. Concentrationsof 100, 200, and 400 mg/kg of bropirimine were used. Interferonlevels were determined in maternal serum, spleen, and wholeembryo extracts and uterine contents were evaluated for survivalof the embryos. Maternal toxicity occurred in all experimentsas evidenced by dose-related decreases in body weight duringthe first 24 hr postdosing. Hematoxicology analyses of maternalserum revealed significant decreases in urea nitrogen, potassium,and albumin, along with increases in aspartate transaminase,alanine transaminase, and total bilirubin, in bropirimine-treateddams as compared to the vehicle controls. In addition, the meansfor maternal thymus weight decreased while the means for spleenweight increased with increasing concentration of bropirimine.As compared to the vehicle controls, interferon titers werehigh in maternal serum, maternal spleen, and, to a lesser extent,whole embryos, 2 hr postdosing, but had decreased or were belowdetectable levels 24 hr postdosing. Embryolethality was pronounced(increases in pre- and postimplantational loss) after a singledose (Gestation Day 3, 4, 5, 8, 9, or 10) of bropirimine, aswell as after 7 or 8 consecutive days (Gestation Days 6–12or 6–13) of treatment. Although embryotoxicity never occurredin these experiments in the absence of pronounced maternal toxicity,the pregnant dams never died as the result of bropirimine treatment,whereas the embryos frequently failed to survive.     

Tγδ Cells and their Subsets in Blood and Synovial Tissue from Rheumatoid Arthritis Patients

We have examined the frequencies of T gamma delta cells in blood, synovial fluids, and synovial membranes of patients with rheumatoid arthritis (RA) and in blood from age-matched controls. Immunocytochemical and immunohistochemical techniques were used with monoclonal antibodies BB3 and A13 to define a major and minor blood subset of T gamma delta cells respectively. Together, these antibodies identify the majority (if not all) of the peripheral blood T gamma delta cells. Significantly lower levels of T gamma delta cells were found in the blood of RA patients compared with controls, whilst higher but not significant numbers were found in the synovial fluids of paired samples. Scattered T gamma delta cells were found only in some synovial membranes with a distribution similar to the T alpha beta cells. Analysis of the two different T gamma delta-cell subsets indicated a ratio of BB3 to A13 of about 5:1 in control and RA blood. However, this ratio was less than 1:1 in the RA synovial fluids and membranes. The migratory nature of the A13+ cells could account for their predominance in these sites. The possible pathological significance of these cells in the rheumatoid synovial fluid and synovial membranes is discussed.     

PHARMACOKINETICS OF SINGLE-DOSE I.V.MORPHINE IN NORMAL VOLUNTEERS AND PATIENTS WITH END-STAGE RENAL FAILURE

Morphine 0.125 mgkg^–1 was administered i.v. to 11 normalsubjects and nine patients with chronic renal failure requiringregular haemodialysis. Plasma morphine concentrations were measuredusing high pressure liquid chromatography (HPLC). Although therewas considerable individual variation in both groups, mean plasmaconcentrations of morphine were significantly higher in thepatients with renal failure for 15 min after administration.The decay of plasma concentration fitted a three-compartmentmamillary pharmacokinetic model in all subjects. Derived values(mean $ SEM) of T^x, volume of distribution of the second compartment(V₂), total volume of distribution at steady state ( V^ss1) andtransfer rate constant from the first to the second compartment(k₁₂) were significantly different between groups. Mean valuesof terminal elimination half-life (T⁷) and total body clearancewere similar in the two groups. It was concluded that eliminationof unchanged morphine is not impaired significantly in patientswith chronic renal failure, although accumulation of morphine-3-glucuronideprobably occurs. Although the pharmacological effect of morphineis not related temporally to plasma morphine concentrations,the higher values in patients with renal failure may be implicatedin their increased sensitivity to the drug