DISEASE-MODIFYING ANTIRHEUMATIC DRUGS IN RHEUMATOID ARTHRITIS: CURRENT CONCEPTS

SUMMARY Disease-modifying antirheumatic drugs are used in virtually all patients with established rheumatoid arthritis. An increasingly large number of new drugs is now available. Furthermore, old therapies are being used in novel ways. Treatment is now begun earlier and patients are rarely left untreated. This report summarises recent developments regarding the drugs currently in use and those that may be available in the near future.     

Responsiveness and calibration of the general well-being adjustment scale in patients with hypertension

We examined the discriminant ability and responsiveness of the General Well-Being Adjustment Scale in patients enrolled in a randomized clinical trial of antihypertensive therapy. We also tried to translate the effects of physical symptoms on general well-being. This secondary analysis used demographic, clinical, physical symptom, and general well-being data for 545 white, male hypertensive patients. General well-being was measured by the General Well-Being Adjustment Scale (GWB) collected on 2 occasions over 8 weeks of treatment. Patients with any one of 14 physical symptoms or problems, compared to those without symptoms, had lower GWB scores (p < 0.003 to p < 0.0001). Decreases of 2.83–8.76 points in GWB scores were observed in patients developing physical symptoms over the 8 week study period (p < 0.05 to p < 0.0001). These effects were demonstrated in patients developing cold sensitivity, sexual problems, chest pain, shortness of breath, loss of taste, nausea, hot or cold spells, numbness and tingling, dry mouth, blurred vision, and dizziness. We conclude that the GWB is responsive to clinically meaningful changes in symptoms and may provide a more complete evaluation of the effects of medical treatment. The GWB is a valid and responsive measure of health status outcomes in the evaluation of antihypertensive treatment.     

Identification of urinary metabolites of 8-methyl-8-azabicyclo- 3,2,1] octan-3-yl 3,5-dichlorobenzoate (MDL 72,222) in the dog and monkey.

The metabolism of 8-methyl-8-azabicyclo- 3,2,1]octan-3-yl 3,5-dichlorobenzoate (MDL 72,222) was studied in the dog and monkey. Four urinary metabolites were detected by HPLC, HPLC/MS, and GC/MS, and were identified by comparison to authentic standards. The major metabolite in the dog, approximately 41% of the administered dose excreted between 0 and 120 hr, was the MDL 72,222-N-oxide. On the other hand, the major metabolite in the monkey was the glycine conjugate of 3,5-dichlorobenzoic acid (greater than 56% of the dose). Seven percent of the dose in the monkey urine was free 3,5-dichlorobenzoic acid. N-Desmethyl MDL 72,222 was present at 2.5 and 1% in the dog and monkey, respectively. Very little (less than 1%) of the parent compound was found in urine. The major pathways of metabolism of MDL 72,222 are N-oxidation, N-demethylation, ester hydrolysis, and amino acid conjugation.     

An approach to fractures of the midface: An interactive tutorial

Purpose: To describe an educational computer aided instruction program dealing with diagnosis and classification of facial fractures. Methods: A program was created for use on Macintosh computers using a graphic presentation package. This program allows for the display of high resolution digitized radiographic images and illustrations, along with integrated voice and text information. Users can interact with the program to review complex concepts or study additional cases. Case material was obtained from selected high quality plain radiographs and computed tomography (CT) scans obtained in the trauma center of one institution, and was scanned on a high resolution digital scanner with image parameters optimized for viewing on the Macintosh high resolution color monitor. Results: The program has been installed in the computer aided instructional laboratories or trauma centers at The University of Texas Health Science Center, Houston; The University of Alabama, Birmingham; Emory University School of Medicine, Atlanta, Georgia; and The University of North Carolina, Chapel Hill. The program is available to radiology residents and medical students rotating on the trauma radiology services at these institutions. Completion of the program requires 30–45 minutes. Conclusion: Based on our initial experience, the program has been used by residents in the training programs of all institutions with favorable results.     

Orthotopic liver transplantation at Groote Schuur Hospital.

We present data on 10 patients (5 men and 5 women, aged 21-56 yrs) with end-stage liver disease or tumour who underwent orthotopic liver transplantation at Groote Schuur Hospital between October 1988 and June 1991. Standard surgical techniques were used for procuring the donor liver, the recipient hepatectomy and the implantation of the liver. The venovenous bypass method was used in all but 2 patients. Postoperative immunosuppression was usually achieved with cyclosporin, azathioprine and low-dose steroids. Six patients were treated with prophylactic OKT3. Rejection episodes were treated with bolus doses of intravenous steroids. The indications for liver transplantation included chronic active hepatitis progressing to cirrhosis (5), biliary cirrhosis in association with inflammatory bowel disease (1), sclerosing cholangitis (2), alpha 1-antitrypsin deficiency (1), and tumour (1). All patients with chronic liver disease had experienced at least one complication, examples of which included encephalopathy, bacterial peritonitis, ascites, variceal bleeding and septicaemia. Serious postoperative complications included acute rejection of the transplanted liver, renal and liver failure that responded to intensive care support and medical management. One patient died on the 11th postoperative day with complications of bleeding oesophageal ulcer, shock and fungaemia. The remaining patients are alive and well 1-31 months after transplantation.     

Using toxicity grades in the design and analysis of cancer phase I clinical trials.

Ethical considerations in a cancer phase I trial require a design allowing determination of the maximum tolerated dose with a minimum number of patients treated at low ineffectual or high overly toxic doses. It would also be advantageous to complete the phase I trial in as short a period of time and with as few patients as possible to allow further resources for later studies in which patients are treated at the optimal dose. Several dose escalation schemes are compared. These are the Fibonacci, two two-stage schemes, and a proposed scheme which uses knowledge of all toxicity grades. Estimates of the maximum tolerated dose are obtained and compared using the dose escalation schemes alone, a logit model, and a proposed mean response model. Confidence intervals using the delta method are obtained from the logit and mean response models. The proposed scheme and the two-stage schemes have the advantage of requiring fewer patients, particularly at low doses. Confidence intervals obtained from the mean response model have better coverage than those from the logit model. Data from a cancer phase I trial of dipyridamole and acivicin is presented to illustrate the methods.     

Dose-Additive Inhibition of Intake of Ethanol by Cholecystokinin and Bombesin

Cholecystokinin (CCK) and bombesin (BBS) are neuropeptides of the brain and gut which have been shown to inhibit intake of ethanol. CCK octapeptide and BBS tetradecapeptide were injected intraperitoneally in both single doses and combinations of doses to determine interactions of the two peptides in the control of consumption of ethanol. Water-deprived rats were given access to 5% w/v ethanol for 30 min, followed by a 30-min access to water, daily. One minute before presentation of ethanol, rats were injected with either saline or one of ten peptide solutions (three of CCK alone, three of BBS alone, and four combinations of both). Results from the injections of single peptides were used to determine predicted inhibitions of the peptide combinations, assuming perfect additivity of doses. None of the actual values of inhibition of intake of ethanol by peptide combinations differed significantly from its predicted additive value. Endogenous CCK-like and BBS-like peptides may suppress intake of ethanol by an additive mechanism of inhibition.     

Functional differences among those high and low on a trait measure of psychopathy.

BACKGROUND: It has been established that individuals who score high on measures of psychopathy demonstrate difficulty when performing tasks requiring the interpretation of other's emotional states. The aim of this study was to elucidate the relation of emotion and cognition to individual differences on a standard psychopathy personality inventory (PPI) among a nonpsychiatric population. METHODS: Twenty participants completed the PPI. Following survey completion, a mean split of their scores on the emotional-interpersonal factor was performed, and participants were placed into a high or low group. Functional magnetic resonance imaging data were collected while participants performed a recognition task that required attention be given to either the affect or identity of target stimuli. RESULTS: No significant behavioral differences were found. In response to the affect recognition task, significant differences between high- and low-scoring subjects were observed in several subregions of the frontal cortex, as well as the amygdala. No significant differences were found between the groups in response to the identity recognition condition. CONCLUSIONS: Results indicate that participants scoring high on the PPI, although not behaviorally distinct, demonstrate a significantly different pattern of neural activity (as measured by blood oxygen level-dependent contrast)in response to tasks that require affective processing. The results suggest a unique neural signature associated with personality differences in a nonpsychiatric population.     

The frequency of vitamin D deficiency in adults with Crohn's disease.

BACKGROUND: Vitamin D deficiency is a putative, pathogenic cofactor in the increase in osteopenia and osteoporosis seen in patients with Crohn's disease. OBJECTIVE: To determine the frequency of low serum 25-hydroxy-vitamin D3 (25-OHD) levels and the associated alterations in bone mineral density in a cohort of adults with Crohn's disease. METHODS: 25-OHD levels were determined in 242 consecutive patients with Crohn's disease seen in two tertiary inflammatory bowel disease referral centres. Bone mineral density was assessed by dual energy x-ray absorptiometry. RESULTS: Nineteen (8%) patients exhibited vitamin D deficiency (25-OHD less than 25 nmol/L) and 52 (22%) patients exhibited vitamin D insufficiency (25-OHD less than 40 nmol/L). Mean T-scores at the lumbar spine, femoral neck, total hip and ultradistal radius in the group with low 25-OHD did not differ from those of the normal 25-OHD group. Serum alkaline phosphatase and parathyroid hormone levels were higher in the low 25-OHD group than in the normal group. Decreased red blood cell (RBC) folate predicted low 25-OHD in male patients, while smoking, RBC folate and serum iron predicted low 25-OHD in female patients. The rate of low 25-OHD deficiency in the winter was significantly higher than that in the summer (11.9% versus 2.8%, respectively). CONCLUSION: Vitamin D-deficient Crohn's disease patients exhibit biochemical evidence of metabolic bone disease, without detectable differences in bone mineral density. Sunlight exposure, nutrition and smoking status were predictors of vitamin D deficiency in this patient cohort.     

Through a glass darkly: the disutility of the DSM nosology of depressive disorders.

OBJECTIVE: To demonstrate that the dimension-weighted DSM-IV model for classifying the depressive disorders lacks utility. METHOD: The logical flaws in classifying the depressive disorders with any severity-based model (which underpin both the DSM-IV and ICD-10 systems) are noted. Integral definitional limitations to the DSM-IV definition of key depressive disorders are identified. It is argued that the DSM-IV classificatory system lacks utility for providing information on etiology and preferential management strategies. An alternative subtyping model is considered. RESULTS: It is asserted that, in practice, the DSM-IV model and criteria lack explanatory power and compromise research and clinical practice. CONCLUSIONS: It is hoped that this article evokes wider debate about modelling and classifying the depressive disorders.