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     

Effects of cholinesterase inhibitors on the neuromuscular blocking action of suxamethonium

Prolonged neuromuscular block occurs when suxamethonium is givenafter neostigmine or pyridostigmine; however, studies of edrophoniumand suxamethonium have yielded conflicting results. We havestudied, therefore, interactions between suxamethonium and allthree anticholinesterases in rats anaesthetized with pentobarbitone.After recovery from an initial bolus of suxamethonium, saline,edrophonium, pyridostigmine or neostigmine was administeredand a second dose of suxamethonium was then given. All threeanticholinesterases prolonged the duration of neuromuscularblock (90% suppression to 50% twitch recovery) to 127(SEM 9)%,127(10)% and 138 (11)% of baseline for edrophonium, pyridostigmineand neostigmine, respectively. Recovery index (25% to 75% twitchrecovery) was increased also to 125 (9)%; 149 (10%) and 185(15)% of baseline, respectively for the three drugs. Presented in part at the 1992 annual meetings of the AmericanSociety of Anesthesiologists and the California Society of Anesthesiologists.     

RESPONSIVENESS OF KEITEL FUNCTIONAL INDEX COMPARED WITH LABORATORY MEASURES OF DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS

This study compares functional changes to change in measuresof disease activity following the introduction of slow-actinganti-rheumatic drugs (SAARD) in patients with active rheumatoidarthritis (RA). Clinical and laboratory variables were simultaneouslymonitored at 6-monthly intervals, over approximately 18 months.Function was measured by a performance testing, the Keitel functionindex (KFI), which was divided into sections representing smalland large joints [and (HFI); wrist (WFI) and limb function index(LFI)]. One-hundred-and-fifteen patients were studied, of whom21 were male. The mean age of the subjects was 49 yr (s.D. ±12) and mean duration of disease 7 yr (S.D. ± 7). Themean KFI at entry was 38 (S.D. ± 18) while at the endof the study it was 31 (s.D. ± 17) (P < 0.0001). Thechange in KFI following therapy correlated with the change inRitchie articular index (RAI) (r = 0.4; P < 0.0001), earlymorning stiffness (EMS) (r = 0.3; P = 0.004), swollen jointcount (JC) (r = 0.4; P = 0.0005). C-reactive protein (CRP) (r= 0.2; P < 0.05) and Lansbury systemic index (LSI) (r = 0.35;P = 0.002), but not with change in Westergren erythrocyte sedimentationrate (ESR) or change in time to onset of fatigue. Multiple regressionanalysis showed that 32% of the variation in KFI at the endof the study could be predicted by a combination of ESR, sulphasalazinetherapy, RAI, disease duration and chloroquine treatment atonset (P < 0.05). When HFI at end of study was the dependentvariable, 21 % of the variation could be predicted by a combinationof ESR, CRP, Lansbury systemic index and JC at onset (P <0.05). The duration of disease did not significantly influencethe potential for change in functional status. This study showedthat detailed measurement of function is important in assessingRA activity. Functional impairment in RA is a dynamic processinfluenced by changes in clinical disease activity with treatment. KEY WORDS: Keitel function index, Disease activity, Outcom, Hand function index     

Dietary Changes Favorably Affect Bone Remodeling in Older Adults

OBJECTIVE: To determine whether dietary counseling to increase milk intake could produce useful changes in the calcium economy and what, if any, other nutrition-related changes might be produced. DESIGN: Randomized, open trial. SUBJECTS/SETTING: Two hundred four healthy men and women, aged 55 to 85 years, who habitually consumed fewer than 1.5 servings of dairy foods per day. Six academic health centers in the United States. INTERVENTION: Subjects were instructed to consume 3 servings per day of nonfat milk or 1% milk as a part of their daily diets, or to maintain their usual diets, for a 12-week intervention period, which followed 4 weeks of baseline observations. MAIN OUTCOME MEASURES: Energy and nutrient intake assessed from milk intake logs and 3-day food records; serum calciotrophic hormone levels at baseline and at 8 and 12 weeks; urinary excretion of calcium and N-telopeptide at 12 weeks. STATISTICAL ANALYSES: Repeated-measures analysis of variance. RESULTS: In the milk-supplemented group, calcium intake increased by 729 +/- 45 mg/day (mean +/- standard error), serum parathyroid hormone level decreased by approximately 9%, and urinary excretion of N-telopeptide, a bone resorption marker, decreased by 13%. Urine calcium excretion increased in milk-supplemented subjects by 21 +/- 7.6 mg/day (mean +/- standard error), less than half the amount predicted to be absorbed from the increment in calcium intake. All of these changes were significantly different from baseline values in the milk group and from the corresponding changes in the control group. Bone-specific alkaline phosphatase level (a bone formation marker) fell by approximately 9% in both groups. Serum level of insulin-like growth factor-1 (IGF-1) rose by 10% in the milk group (P < .001), and the level of insulin-like growth factor binding protein-4 (IGFBP-4) fell slightly (1.9%) in the milk group and rose significantly (7.9%) in the control group (P < .05). APPLICATIONS/CONCLUSIONS: The changes observed in the calcium economy through consumption of food sources of calcium are similar in kind and extent to those reported previously for calcium supplement tablets. The increase in IGF-1 level and the decrease in IBFBP-4 level are new observations that are beneficial for bone health. Important improvements in skeletal metabolism can feasibly occur in older adults by consumption of food sources of calcium. Dietitians can be confident that food works, and that desired calcium intakes can be achieved using food sources.     

Residents' perspectives of their first 2 weeks in a long-term care facility

• ? This study investigated residents' perspectives of their first 2 weeks in a long-term care facility (LTCF). Twelve residents were interviewed to determine their experiences during the first 2 weeks, their needs, priorities and expectations, and their views about how relocation from home could be facilitated. The constant comparative method of qualitative analysis (Glaser & Strauss, 1967) was used.
• ? Qualitative analysis of the audiotaped interviews revealed four main categories: emotional reactions, transition activities, reflecting on their situation, and connecting with a personal philosophy.
• ? Residents' responses indicated that if they had actively participated in the decision to be admitted, the adjustment to the LTCF was easier. Connecting with a personal philosophy was also a significant factor.
• ? Nursing implications include recognition of the importance of preparing residents for admission, involving them in the decision, and listening to their perspectives throughout the relocation experience.

     

Protection against Acetaminophen Hepatotoxicity by a Single Dose of Clofibrate: Effects on Selective Protein Arylation and Glutathione Depletion

Previous reports demonstrated that repeated administration ofperoxisome proliferators protects against acetaminophen (APAP)hepatotoxicity in mice. This protection was associated witha decrease in APAP's selective protein arylation and glutathionedepletion. This study was conducted to determine if a singledose of clofibrate (CFB), rather than repeated doses, wouldsimilarly prevent APAP toxicity. CD-1 male mice received a singledose of 500 mg CFB/kg and controls were given corn oil 24 hrprior to APAP challenge. After an 18-hr fast, mice were challengedwith 800 mg APAP/kg (in 50% propylene glycol) and killed at4 or 12 hr. Other mice similarly pretreated were killed withoutAPAP challenge. The results showed that pretreatment with asingle CFB dose significantly decreased APAP-induced hepatotoxicity.At 12 hr after APAP plasma sorbitol dehydrogenase activity andthe severity of hepatocellular necrosis were decreased in CFBpretreated mice. Surprisingly, no differences in hepatic nonproteinsulfhydryl (NPSH) depletion or selective arylation of targetproteins in cytosol were observed at 4 hr after APAP challenge.Neither did a single dose of CFB significantly alter hepaticNPSH content prior to APAP challenge. These results indicatethat protection against APAP hepatotoxicity by CFB does notrequire repeated administration, and the absence of significantalterations in APAP's selective protein arylation or glutathionedepletion suggests that the protection against APAP hepatotoxicityafter a single treatment with CFB may differ mechanisticallyfrom the protection observed after repeted CFB dosing.     

SUSPECTED CUTANEOUS DRUG TOXICITY IN RHEUMATOID ARTHRITIS--AN EVALUATION

Cutaneous toxicity from drugs used to treat RA is a major perceivedproblem. Over a 2-yr period we have prospectively reviewed 114patients with a suspected adverse cutaneous reaction to anti-rheumaticdrugs. In 71 (62%), the rash was thought to be unrelated todrug therapy. This group included 10 in whom the rash had resolvedbefore review (usually < 1 week), 38 with a rash relatedto their rheumatoid disease and 23 with eruptions unrelatedto either drugs or arthritis. Fortythree (38%) patients hadrashes thought to be related to their drug therapy. Gold therapy(both oral and intramuscular) was implicated most frequently(31 patients). However, the majority of these (23) had a pityriasiform/discoideczematous eruption that responded to potent topical steroidsoccasionally with a reduction in gold dosage. In this sample it was possible to continue drug therapy in 82%of patients with what were initially thought to be cutane ousadverse drug reactions. Careful evaluation should allow a majorityof patients to continue drug therapy from which they are oftengaining benefit. KEY WORDS: Rheumatoid arthritis, Cutaneous drug toxicity, Vasculitis, Capillaritis, Pruritus, Asteatotic eczema, Pityriasis rosea, Discoid eczema, Pemphigus, Alopecia     

A DOUBLE-BLIND STUDY OF THE EFFECTIVENESS OF LOW LEVEL LASER TREATMENT OF ROTATOR CUFF TENDINITIS

Thirty-five patients with rotator cuff tendinitis were randomlyallocated to active (CB Medico Master III 830 nm Ga As AL diode)laser or dummy laser treatment twice weekly for 8 weeks. Movementrange, painful are score, resisted movement score and responsesto visual analogue scales for night pain, rest pain, movementpain and functional limitation were measured second weekly.All responses improved from baseline but there was no differencebetween the two groups. These results fail to demonstrate theeffectiveness of laser therapy in rotator cuff tendinitis. KEY WORDS: Rotator cuff tendinitis, Laser, Treatment     

The Noninvasive Mouse Ear Swelling Assay: II. Testing the Contact Sensitizing Potency of Fragrances

The Noninvasive Mouse Ear Swelling Assay. I. Refinements forDetecting Weak Contact Sensitizers. THORNE, P. S., HAWK, C,KAUSZEWSKI, S. D., AND GUINEY, P. D. (1991). Fundam. Appl. Toxicol.17, 790–806. The noninvasive mouse ear swelling assay(MESA) is a model for delayed-type hypersensitivity that holdspromise as a testing protocol for allergic contact dermatitis(ACD). The MESA employs only topical sensitization on the abdomenand does not use injections, adjuvants, anesthesia, occlusion,or disruption of the stratum comeum. Five days after induction,the ears are challenged topically and ear swelling measurementstaken at 24,48, and 72 hr indicate the extent of ACD. In thisstudy, refinements of the assay were explored in BALB/cBy miceusing dinitrofluorobenzene (DNFB) and dinitrochlorobenzene (DNCB).A complete dose-response curve was developed for DNFB and thedose which sensitized half the mice in a group (SD50, 0.001%,w/v) was used to test noninvasive enhancement protocols. Severaltriple-dose protocols tested produced no increase in responsivenessand daily dosing showed a trend toward tolerance induction yielding20% positive responses. Dietary vitamin A supplementation produceda dramatic enhancement of the responses: ear thickness increasewas doubled and the SD50 sensitized 94 to 100% of the mice inthe vitamin A groups. We conclude that the MESA allowed identificationof ACD potency for known sensitizers at very low concentrationswhich do not produce ACD with other techniques. The importanceof dose-response studies for avoiding the high-dose reduced-responseregion was also shown. Based on the observation that the vitaminA-augmented MESA was considerably more sensitive than with regularfeed, a companion study (P. S. THORNE, C. HAWK, S. D. KALISZEWSKI,P. D. GUINEY, Fundam. Appl. Tox. 17, 807–820, 1991) presentstests of the enhancements to the MESA developed in this work,using weak sensitizers and complex mixtures.