Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response

1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite >6 months of SASP treatment.
2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two- compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis.
3. Pharmacokinetics of MTX without vs with SASP, means±s.d. were as follows: AUC: 673±179 vs 628±210 (95% confidence interval [CI] of the difference was −71 to 159) ng ml⁻¹ h, MRT: 5.2±1.3 vs 5.2±1.1 (95% CI −0.4 to 0.4) h, t½,z: 4.3±1.1 vs 4.2±1.1 (95% CI −0.3 to 0.5) h, V /F: 59.3 ±29.3 vs 65.5±25.3 (95% -23.8 to 11.4) l, CL/F: 12.3±5.0 vs 13.5±4.8 (95% CI −4.5 to 2.3) l h⁻¹. CL_R/F: 6.2±1.3 vs 6.3±2.1 (95% CI −1.3 to 1.1) l h⁻¹. All P values were ≥0.3.
4. A weak correlation existed between the change of ESR and the MRT, the t½,z and the V /F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05<P<0.1).
5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables of MTX.

     

The mechanism of directional coronary atherectomy

An attempt was made to assess the mechanism of directional coronaryatherectomy using different methods of analysis. Quantitativecoronary angiography was used as the gold standard to assessthe immediate results of atherectomy, and a comparative quantitativeanalysis of atherectomy and balloon angioplasty was made. Todetermine whether the post-atherectomy cross-sectional areais close to a circle, we compared the area measurements obtainedby edge detection with those obtained by videodensitometry.Finally, the extent of a ‘Dotter’ effect was establishedby quantitative angiography following crossing the stenosiswith the atherectomy device. For the purpose of this study,the results of the first 113 successful atherectomy procedureswere reviewed. In matched lesions, directional atherectomy induceda greater increase in minimal luminal diameter than balloonangioplasty (1.6 mm vs 0.8 mm; P < 0.0001 However, this luminalimprovement is due to a substantial ‘Dotter’ effectinduced by the bulky atherectomy device. Following atherectomy,only a slight difference in cross-sectional area measurementsbetween edge detection and videodensitometry (mean difference:0.28 mm² was found. Histologic examination of an atherectomizedcoronary artery showed a near-circular post atherectomy areageometry. In conclusion, directional atherectomy is a very effectivedevice with a substantially better initial result than balloonangioplasty. However, insertion of this bulky device itselfcauses an important ‘Dotter’effect.     

CALCITONIN GENE-RELATED PEPTIDE II, SUBSTANCE P AND VASOACTIVE INTESTINAL PEPTIDE IN PLASMA AND SYNOVIAL FLUID FROM PATIENTS WITH INFLAMMATORY JOINT DISEASE

Immunoreactive plasma and synovial fluid concentrations of calcitoningene-related peptide II (CGRP II), substance P and vasoactiveintestinal peptide (VIP) were measured in patients with osteoarthritis,gout and rheumatoid arthritis. Significantly higher levels ofCGRP II and substance P and VIP-like immunoreactivity levelsin synovial fluid were found in gout as well as CGRP II, substanceP and VIP-like immunoreactivities in rheumatoid arthritis whencompared to those in osteoarthritis. Plasma CGRP II, substanceP and VIP-like immunoreactivity levels showed no significantdifferences among patients in the three different groups ofarthritis. Our results suggest that these neuropeptides releasedfrom peripheral nerve endings into the synovial cavity probablyplay a pathogenic role in human joint inflammation. KEY WORDS: Rheumatoid arthritis, Gout, Calcitonin gene-related peptide II, Substance P, Vasoactive intestinal peptide, Synovial fluid     

Tissue reactions to long-term electrical stimulation of the cerebellum in monkeys.

Light and electron microscopic analyses were carried out on the stimulated and unstimulated paravermal cortices of six rhesus monkeys that had electrodes implanted on their cerebella for 2 months. The electrodes and the stimulation regime (10 p.p.s.: 8 min on, 8 min off) were similar to those used to stimulate the human cerebellum for treatment of certain neurological disorders. Mere presence of the electrode array in the posterior fossa for 2 months resulted in some meningeal thickening, attenuation of the molecular layer, and loss of Purkinje cells immediately beneath the electrode array. There was no evidence of scarring. After 205 hours of stimulation (7.35 X 10(6) pulses) over 18 days, a charge of 0.5 muC/ph or estimated charge density of 7.4 muC/sq cm/ph resulted in no damage to the cerebellum attributable to electrical stimulation per se. Such a charge/phase is about five times the threshold for evocation of cerebellar efferent activity, and might be considered "safe" for stimulation of human cerebellum. Charge density/phase and charge/phase were directly related to increased cerebellar injury in the six other cerebellar cortices stimulated. Leptomeningeal thickening increased with increased charge density. Injury included severe molecular layer attenuation, ongoing destruction of Purkinje cells, gliosis, ongoing degeneration of myelinated axons, collagen intrusion, and increased levels of local polysaccharides. In all cases, even with damage that destroyed all conducting elements beneath the electrodes, there was no damage further than 1 to 2 mm from the edges of the electrode arrays.     

Laparoscopic management of bile duct stones.

Although it may seem that laparoscopic cholecystectomy has revolutionized the way we approach the patient with stones in the gallbladder and bile ducts, only a few rules have really changed. Fluoroscopic cholangiography, a requirement for radiologists and gastroenterologists performing percutaneous transhepatic cholangiography and ERCP, is slowly finding its way into the operating room. No longer is a "palpable stone" a common indication for common bile duct exploration. Most importantly, it is not necessary to make an incision into the bile duct to remove the majority of bile duct stones. The transcystic approach will clear the duct in 85% to 90% of all patients, sparing them extra hospitalization, a T-tube, and the risk of creating a bile duct stricture during sutured closure of the choledochotomy.     

VOLTAGE FIELDS SURROUNDING NEEDLES USED IN REGIONAL ANAESTHESIA

Using a bench model, we have studied the voltage fields surroundingboth insulated and uninsulated needles used in regional anaesthesia.The findings were compared with earlier computer predictionswhich suggested that the fields would be markedly differentfor the two types of needle. The results confirm that the fieldsdiffer markedly and suggest that the use of insulated needlesmay not necessarily improve the accuracy of nerve location andthat uninsulated needles may be more appropriate. ^*Present addresses: Department of Anaesthetics, Hull Royal Infirmary,Hull, Humberside. Droitwich Knee Foundation, Saga House, SansomePlace, Worcester Present addresses: Droitwich Knee Foundation, Saga House, SansomePlace, Worcester.     

FUNCTIONAL ROLE OF CARDIAC PRESYNAPTIC α2-ADRENORECEPTORS IN THE BRADYCARDIA OF α-ADRENORECEPTOR AGONISTS IN PENTOBARBITONE- AND URETHANE-ANAESTHETIZED NORMOTENSIVE RATS

• 1 The relative potencies of 6 α-adrenoreceptor agonists, with differing physicochemical properties, at cardiac presynaptic α-adrenoreceptors were determined by measuring their ability to reduce the tachycardia produced by stimulation of the cardiac sympathetic nerves in pithed rats. The compounds studied were clonidine, B-HT 933 (azepexole), oxymetazoline, St 91, naphazoline and DPI.
• 2 The bradycardia produced by the same compounds in bilaterally vagotomized, urethane- or pento-barbitone-anaesthetized normotensive rats were also compared. The relative order of presynaptic potency appeared similar to that observed for the bradycardic activity of the compounds in urethane- and pento-barbitone-anaesthetized rats. In pentobarbitone-anaesthetized rats all compounds evoked a maximal effect of 18–20% reduction in heart rate. In urethane-anaesthetized rats, however, a difference was observed between clonidine and azepexole on the one hand and oxymetazoline, St 91, naphazoline and DPI on the other hand. The former induced a 20–22% reduction in cardiac frequency, whereas the latter diminished heart rate by 10–16% only. In vagotomized, bilaterally adrenalectomized, urethane-anaesthetized rats, clonidine, St 91, naphazoline and azepexole evoked a 25% reduction in heart rate, whereas a 20% reduction was observed for DPI and oxymetazoline.
• 3 A radio-enzymatic determination of plasma catecholamines demonstrated that under urethane-anaesthesia plasma adrenaline concentrations were significantly elevated over the values observed in pentobarbitone-anaesthetized rats. This rise in plasma adrenaline was related to the amount of urethane used. In urethane-anaesthetized, bilaterally adrenalectomized rats, plasma adrenaline was not significantly elevated.
• 4 These findings demonstrate the involvement of cardiac presynaptic α₂-adrenoreceptors in the acute bradycardia, evoked by the α-adrenoreceptor agonist upon intravenous application to pentobarbitone-anaesthetized, normotensive rats. In urethane-anaesthetized rats, however, the functional role of the cardiac presynaptic α₂-adrenoreceptors may be obscured as a result of the high plasma adrenaline levels observed in these animals.

     

IMPAIRMENT BY NIFEDIPINE OF VASOPRESSOR RESPONSES TO STIMULATION OF POSTSYNAPTIC α2-ADRENORECEPTORS IN GANGLION-BLOCKED RABBITS. FURTHER EVIDENCE FOR THE SELECTIVE INHIBITION OF POSTSYNAPTIC α2-ADRENORECEPTOR-INDUCED PRESSOR RESPONSES BY CALCIUM ANTAGONISTS

• 1 After ganglionic blockade and bilateral vagotomy, vasopressor responses induced by activation of postsynaptic α₁- and α₂-adrenoreceptors were elicited in the intact circulatory system of rabbits.
• 2 The hypertensive effects of the selective stimulating agents methoxamine (α₁-agonist) and B-HT 920 (α₂-agonist) were effectively antagonized by the adrenoreceptor antagonists prazosin and yohimbine, respectively. These findings confirm the existence of two types of postsynaptic α-adrenoreceptors (α₁-and α₂-type) in vascular smooth muscle of rabbits.
• 3 The calcium antagonistic drug nifedipine did not affect the maximal increase in diastolic pressure brought about by methoxamine, whereas it strongly inhibited the hypertensive effects of B-HT 920.
• 4 It is concluded that this confirmation of the selective inhibition of postjunctional α₂-adrenoreceptor-mediated vasopressor responses by a calcium antagonistic drug, such as nifedipine, indicates that this activity constitutes a general phenomenon. This finding supports the hypothesis that an influx of extracellular calcium is necessary for the vasoconstriction mediated by postsynaptic α₂-adrenoreceptors.