The consequences of H2 receptor antagonist — piroxicam coadministration in patients with joint disorders

Summary A randomised crossover study was performed in subjects with rheumatoid arthritis (or other arthropathies) to investigate if any alteration in the steady pharmacokinetics of the NSAID piroxicam (a drug which is extensively metabolised via cytochrome P450) or its major metabolites occurred as a result of coadministering either cimetidine or nizatidine.Twelve females and 2 males with mean age, weight, and albumin concentrations of 58 years, 61 kg, and 40 g·L^–1 respectively, completed the study. Comparisons were made between the following parameters: plasma piroxicam AUCs [AUC_0-24(P)], plasma 5-hydroxypiroxicam AUCs [AUC_0-24(5-OHP)], the ratio of these i.e. AUC_0-24(5-OHP):AUC_0-24(p), the % piroxicam daily dose excreted in urine as 5-hydroxypiroxicam (before and after glucuronidase incubation); and the mean of the steady state trough piroxicam, and 5-hydroxypiroxicam concentrations (obtained during each study phase in addition to the wash-out period).A statistically significant difference as a result of initiating either cimetidine or nizatidine was obtained only for the ratio AUC_0-23(5-OHP):AUC_0-24(P). This was indicative of a weak potential to inhibit piroxicam hydroxylation.No clinically significant alteration in the steady state pharmacokinetics of piroxicam occurred in these subjects as a result of cimetidine or nizatidine coadministration. Consequently it is unlikely that any adverse events would arise from these combinations.     

Smoking and coffee intake following alcohol withdrawal in alcoholic inpatients

The aim of this study was to assess alcoholic inpatients' smoking and coffee intake variation following withdrawal. Only moderate smokers (less than 30 cigarettes/day) showed a significant increase of cigarette consumption after alcohol withdrawal. However, their urinary cotinine level did not vary, suggesting a behavioral, and not biological, compensation through smoking following alcohol withdrawal. Heavy smokers (30 cigarettes/day or more) showed no significant clinical or biological variation of smoking behavior. Coffee consumption increased after alcohol withdrawal in all patients, irrespective of smoking habits.     

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg-1. 2. Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 +/- 9.6 ml min-1 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. The mean residence time and half-life were 20.9 +/- 1.4 and 14.4 +/- 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 +/- 0.18 l kg-1. 3. No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4. In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5. These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.     

Innovative Laboratory Techniques to Facilitate Processing of Large Mohs Cases

Background Processing multiple tissue sections in large Mohs cases is time consuming and labor intensive.
Objective To present innovative laboratory techniques to facilitate processing of large Mohs cases.
Methods A method for processing a large dermatofibrosarcoma protuberans Mohs case is outlined.
Results Modifications in tissue processing and equipment employed in a large Mohs case are presented.
Conclusion Innovative modifications to the standard Mohs laboratory technique can facilitate processing of large Mohs cases, resulting in high-quality, rapid frozen sections while optimizing efficiency.     

The interaction of parafluorohexahydrosiladiphenidol at muscarinic receptors in vitro

1. The antagonistic actions of parafluorohexahydrosiladiphenidol (pFHHSiD) at muscarinic receptors has been studied in cardiac muscle, smooth muscle and cell culture preparations. In this paper, the classification scheme of Doods et al. (1987) is employed. This scheme is based upon differential affinities of muscarinic antagonists. pFHHSiD exhibited high pA2 values at M3 receptors mediating contractions of guinea-pig ileum and oesophageal muscularis mucosae (7.8 and 8.2 respectively) whereas low values were determined at M2 receptors mediating negative inotropic responses in guinea-pig atria (6.0). Intermediate pA2 values were determined at M1 receptors mediating contractions of the canine femoral and saphenous veins. 2. The pA2 values of pFHHSiD at receptors mediating endothelial-dependent relaxation of rat aortic rings, rabbit jugular vein and canine femoral artery (7.6-7.9) were similar to those determined on the ileum. However, the pA2 values of pFHHSiD at receptors mediating contractions of the guinea-pig trachea (7.1), which has been previously shown to possess M3 receptors, were different from those determined in the ileum. 3. The similarity in pA2 values of pFHHSiD between the M3 receptors in guinea-pig ileum and the receptors mediating endothelial-dependent relaxations provide further evidence for the role of M3 receptors in this vascular response. Taken together, pA2 values for pFHHSiD range from 7.1 to 8.2, depending upon the M3 preparation used. The selectivity of the compound therefore for the M3 versus the M2 muscarinic receptor ranged from 13 to 163 fold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety of GM-CSF in Patients with AIDS: A Review of the Literature

We performed a literature search for all clinical studies reporting outcomes in patients with the acquired immunodeficiency syndrome (AIDS) receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) for any indication. Safety outcomes included human immunodeficiency virus replication, immune status, and frequency of opportunistic infections and neoplasms. Data were synthesized qualitatively. We identified 22 studies (274 patients): 12 addressed AIDS neutropenia, 8 AIDS cancer therapy, and 2 opportunistic infections. Viral burden was assessed by serum p24Ag in 15 studies. Nine reported no change in levels, three net decreases, and three net increases. All studies showing net increases involved patients receiving GM-CSF without a concurrent antiretroviral. The CD4 counts were unchanged in 5 studies, increased in 3, and not reported in 14. The incidence of neoplasms or new opportunistic infections was low. The literature suggests no increased risk of viral replication or clinical deterioration in patients with AIDS who take GM-CSF concurrently with zidovudine.     

Auditory Perception and the Control of Spatially Coordinated Action of Deaf and Hearing Children

From birth onwards, auditory stimulation directs and intensifies visual orientation behaviour. In deaf children, by definition, auditory perception cannot take place and cannot, therefore, make a contribution to visual orientation to objects approaching from outside the initial field of view. In experiment 1, a difference in catching ability is demonstrated between deaf and hearing children (10-13 years of age) when the ball approached from the periphery or from outside the field of view. No differences in catching ability between the two groups occurred when the ball approached from within the field of view. A second experiment was conducted in order to determine if differences in catching ability between deaf and hearing children could be attributed to execution of slow orientating movements and/or slow reaction time as a result of the auditory loss. The deaf children showed slower reaction times. No differences were found in movement times between deaf and hearing children. Overall, the findings suggest that a lack of auditory stimulation during development can lead to deficiencies in the coordination of actions such as catching which are both spatially and temporally constrained.     

Estimation of apparent agonist affinity constants using desensitization of the ileal muscarinic receptor

The effects of short-term desensitization of muscarinic receptors and decreasing the extracellular calcium concentration have been studied using the isolated guinea pig ileum. Desensitization required stimulation of the receptor and was more marked against agonists of low intrinsic efficacy. The process was non-specific in that the responses to histamine were also affected. Application of null methods of analysis to pre- and postdesensitization concentration-response curves enabled an affinity constant to be derived. The values were consistently higher than those estimated using the irreversible antagonist, phenoxybenzamine. In contrast application of null methods to concentration-response curves in normal and low calcium concentrations enabled an affinity constant for pilocarpine to be calculated, which was very similar to that obtained using the irreversible antagonist. It is concluded that desensitization cannot be used to determine agonist affinity constants inasmuch as it results in overestimations.     

Regional Variation in Wound Contraction of Mohs Surgery Defects Allowed to Heal by Second Intention

BACKGROUND: The phenomenon of wound contraction results in a decrease in wound size and a healed scar significantly smaller than the original defect. OBJECTIVE: This study was undertaken (1) to determine the amount of wound contraction in Mohs surgery defects allowed to heal by second intention, (2) to evaluate for regional differences in wound contraction based on the facial anatomic zones for second intention healing described by Zitelli, and (3) to determine whether regional differences in wound contraction account for observed differences in cosmetic outcome. METHODS: One hundred sixty secondarily healed Mohs surgery defects limited to the head and neck having a wound age of greater than 12 weeks in 102 consecutively examined patients were carefully measured with a tissue caliper. The percent wound contraction was calculated and compared for each Zitelli anatomic subunit. The final shape of the wound (quantitatively described) and the cosmetic acceptability (subjectively rated by the patient and examiner) were also compared with the percent wound contraction for each anatomic area. RESULTS: Both NEET (concave surface of the nose, eye, ear, and temple) and FAIR (forehead, antihelix, eyelids, and the remainder of the nose, lips, and cheeks) areas were identical in terms of mean wound contraction (74%), cosmetic acceptability (97%), and conversion to a wound shape with a ratio of maximal length to width of greater than 3.0 (fusiform and linear shapes) (52%). NOCH areas (convex surface of the nose, oral lips, cheeks and chin, and the helix of the ear) demonstrated less wound contraction (66%), cosmetic acceptability (78%), and fusiform-linear conversion (29%). Subset differences and variables that appear to influence wound contraction are discussed. Secondarily healed wounds in areas with one or more positive contraction variables contract 75%, whereas defects in areas with negative contraction variables contract 55%. CONCLUSIONS: Regional differences in wound contraction of secondarily healed head and neck wounds exist and account for some differences in cosmetic acceptability. Scar location, regardless of the degree of wound contraction, is the most important factor for the final cosmetic outcome.     

The pharmacology of recombinant GABAA receptors containing bovine alpha 1, beta 1, gamma 2L sub-units stably transfected into mouse fibroblast L-cells.

1. Responses to gamma-aminobutyric acid (GABA) were evoked in mouse fibroblast L-cells stably transfected with bovine, alpha 1, beta 1, gamma 2L sub-units of the GABAA receptor. Expression was stimulated via a steroid-inducible promoter system. 2. In near symmetrical intracellular and extracellular chloride concentrations, GABA evoked inward currents at negative holding potentials that reversed at +5 mV and displayed slight outward rectification. Concentration-response curves were fitted well by the logistic equation. GABA had a pEC50 = 5.1 +/- 0.1 and the curves had a slope of 1.9 +/- 0.1. 3. Responses to GABA were antagonized by bicuculline, picrotoxin and penicillin. The action of bicuculline was competitive (pA2 = 6.4) whilst the block by picrotoxin was uncompetitive and strongly agonist-dependent. 4. Benzodiazepine receptor agonists potentiated responses to 3 microM GABA. The rank order of potency was FG 8205 > flunitrazepam > zolpidem > C1218872. FG 8205 and C1218872 produced markedly lower maximal potentiations with efficacies 0.4 and 0.6 x that of flunitrazepam, respectively. The potencies of zolpidem and C1218872 observed are in agreement with the BZ1 type pharmacology of this sub-unit combination. The potentiation of GABA by flunitrazepam was antagonized by flumazenil with a Ki of 3.8 nM. 5. GABA responses were potentiated in the presence of pentobarbitone and alphaxalone. The response was also noticeably broadened by these compounds due to a decrease in the response decay rate. Concentrations of pentobarbitone of 100 microM and above evoked an inward current in the absence of GABA. Alphaxalone up to 10 microM did not evoke a direct response.(ABSTRACT TRUNCATED AT 250 WORDS)