Rheumatoid arthritis: a possible sex bias in commencing second-line treatment.
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Antirheumatic Agents↗
Biomedical subjects
J G Larkin
Publications and source records attributed to J G Larkin.
Miscellaneous neurologic, cardiac, pulmonary, and metabolic disorders with rheumatic manifestations.
Problems both old and new are featured in this year's selection of rheumatologic aspects of miscellaneous diseases. Paralysis of one or more limbs can lead to many musculoskeletal complications, and the approach of Auguste Dejerine-Klumpke in 1918 can be compared with that of the present-day physician. The reappearance of rheumatic fever continues to excite interest. The specificity of the modified Jones criteria has been questioned, as have the benefits of long-term antibiotic prophylaxis following an attack of the disease. Meanwhile, metabolic disorders may be the first diseases to come under novel scrutiny using the techniques of genetic engineering, with outstanding possibilities for advancing both understanding and treatment. Dermatologic diseases other than psoriasis may be associated with arthropathy. Many of these symptom complexes may be variants of the recently described SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome.
Cardiovascular Diseases↗
Five years of anticonvulsant monitoring on site at the epilepsy clinic.
The influence of antiepileptic drug monitoring on site at the epilepsy clinic was assessed in a prospective way by recording physicians' decisions before and after the drug concentration became available over the five-year period including 1986 to 1990. A total of 2,857 assays (1,121 carbamazepine, 798 phenytoin, 622 sodium valproate, and 72 phenobarbital) were performed during 2,696 hospital attendances on 618 epileptic patients. A gradual reduction in the proportion of visits monitored annually was observed (1986: 42%; 1987: 51%; 1988: 44%; 1989: 39%; 1990: 28%; p < 0.01). In 481 (17.8%) visits a change in management resulted from knowledge of the drug concentration. This was not an automatic response, as a large minority of unexpected results did not produce such an alteration. The proportion of decisions to adjust the drug dose after an unexpected result, however, tended to increase over the years of the study (1986: 43%; 1987: 70%; 1988: 60%; 1989: 78%; 1990: 54%; p < 0.01). Changes in anticonvulsant dose following an unexpected result were observed in "low" (59%), "therapeutic" (61%), and "high" (52%) concentration categories. Possible benefit for patients can be inferred from the observation that more assay results fell within the target range in the last (61%) compared with the first (33%) year of monitoring (p < 0.01).
Anticonvulsants↗
Peripheral benzodiazepine receptors in platelets of epileptic patients.
Tolerance to the anticonvulsant effect of benzodiazepines is likely to involve changes at the central benzodiazepine-GABA receptor complex. Peripheral benzodiazepine receptors (pBZRs), which can be measured in platelets, may also be involved. Using a binding assay with [3H]-PK 11195 as radioligand, pBZRs were assayed in platelets of patients taking a variety of antiepileptic drugs (AEDs). Comparisons were made with untreated patients. pBZR receptor density (mean +/- s.e. mean) was increased vs controls (8083 +/- 557 fmol mg-1 protein) in the platelets of patients taking a polypharmacy regime including the benzodiazepine clobazam (12661 +/- 1011 fmol mg-1 protein, P < 0.005) and also in those receiving sodium valproate as monotherapy (15003 +/- 1756 fmol mg-1 protein, P < 0.01). The significance of these findings is unclear, but the use of a specific pBZR antagonist may be a promising avenue for investigating the mechanism of BZ tolerance and its prevention.
Adolescent↗
Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam.
Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [3H] PK 11195 (peripheral) and [3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.
Animals↗
Rapid tolerance to acute psychomotor impairment with carbamazepine in epileptic patients.
Thirteen patients with newly diagnosed epilepsy performed a battery of psychomotor function tests before and during the first 12 weeks of carbamazepine (CBZ) therapy. Movement time (P less than 0.025), total choice reaction time (P less than 0.025), finger tapping rate (P less than 0.005) and number cancellation (P less than 0.05) were all significantly impaired after 1 week's treatment, but had returned to baseline by 4 weeks. Mean (+/- s.d.) serum CBZ concentrations and those of its active metabolite CBZ 10,11 epoxide (CBZ-E) were comparable at 1 (CBZ: 8.5 +/- 2.1 mg l-1, CBZ-E: 1.1 +/- 0.68 mg l-1) and 4 weeks (CBZ: 8.1 +/- 4.4 mg l-1, CBZ-E: 0.93 +/- 0.27 mg l-1). These results suggest the rapid development of tolerance to the acute deleterious psychomotor effects of CBZ.
Adolescent↗
Miscellaneous neurologic, cardiac, pulmonary, and metabolic disorders with rheumatic manifestations.
This review discusses miscellaneous diseases with rheumatic manifestations, and out of necessity many rarities are delineated, eg, the Charcot-type joints accompanying congenital sensory neuropathy with anhidrosis or the little-known arthritides that can result from severe acne. Of more general interest is a recent study showing that rheumatic disorders may underlie many neurologic admissions. In cardiology, the main point of interest is a possible resurgence of acute rheumatic fever, occurring first in the United States. Physicians should be alert to this possibility, particularly with the importance of prophylactic antibiotics. Finger clubbing and hypertrophic osteoarthropathy remain unexplained manifestations of pulmonary disease provoking an "International Workshop" devoted to their study. Platelet-derived growth factors may be the favorite candidate. Metabolic disorders with rheumatic complaints include the storage diseases. Some advances in imaging and assessment have been made, and the benefits of liver transplantation are the subject of another report. Other small-print causes of rheumatic complaints include drug abuse, whose protean manifestations include many resembling vasculitic or granulomatous disease.
Adolescent↗
Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.
1. Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2. Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4. Elimination half-lives (mean +/- s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 +/- 1.1 h; after 13.9 +/- 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 +/- 2.2 mumol l-1) were higher than predicted (16.5 +/- 4 mumol l-1). 5. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6. OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.
Adult↗
Myoclonic epilepsy--pitfalls in diagnosis and management.
Three cases of myoclonic epilepsy presenting in adolescence are described. Seizures were uninfluenced by treatment with carbamazepine. Substitution of sodium valproate in early adult life resulted in all becoming seizure-free. A high degree of clinical awareness is required in making the correct diagnosis and in choosing appropriate therapy for this form of epilepsy which can present with generalised tonic-clonic or partial seizures.
Adolescent↗
Managing seizures in the casualty department.
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Adolescent↗
Cognitive function in adult epileptic patients established on anticonvulsant monotherapy.
A battery of psychometric tests was administered to 110 patients with epilepsy and to 24 non-epileptic controls. Eighty-four patients had been established on treatment with a single anticonvulsant drug (35 carbamazepine (CBZ), 30 sodium valproate (VPA), 19 phenytoin (PHT)) at unaltered dosage for the previous 3 months. The remaining 26 patients were untreated at the time of study. No individual test discriminated between the groups. Tests were converted to standard scores and summated to give overall psychomotor, memory and side-effect assessments. There were no important differences between the performances of untreated epileptic patients and non-epileptic controls. The CBZ-treated patients had poorer psychomotor scores than both control groups and the VPA-treated patients (all P less than 0.05). The PHT patients scored less well on the composite memory scale than did VPA patients and non-epileptic controls (both P less than 0.05). There were no significant differences in subjective side-effects among the groups. This study demonstrated that anticonvulsant monotherapy has little effect on overall cognitive function in patients tolerating treatment. Psychomotor performance appeared to be selectively influenced by CBZ and memory impaired by PHT. VPA may be the drug to chose when cognitive function is an important consideration. Different cognitive modalities can be affected by different first-line anticonvulsants and this should be taken into account when choosing the most appropriate drug for an individual patient.
Adolescent↗
Acute psychosis with carbamazepine and sodium valproate.
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Acute Disease↗
Thyroid hormone concentrations in epileptic patients.
Anticonvulsants are associated with decreased serum thyroid hormone concentrations. We have studied thyroid function in 54 epileptic patients on a variety of drugs (19 on carbamazepine, 13 on phenytoin, 10 on sodium valproate, 12 on polypharmacy). For comparison, 14 untreated epileptics and 11 healthy unmedicated volunteers were included as controls. Total thyroxine (T4) concentrations were reduced in patients taking enzyme-inducing drugs (carbamazepine and/or phenytoin) compared with both controls and patients taking sodium valproate. Similar differences were shown with each individual drug. All nine patients whose circulating T4 was below the lower limit of the reference range were taking enzyme inducers. Free thyroxine concentrations were also reduced in individuals treated with carbamazepine and phenytoin with five values falling beneath the reference range. Tri-iodothyronine and thyrotropin appeared unaffected by anticonvulsant administration. Thyrotropin releasing hormone stimulation revealed no true hypothyroidism. The lowering effect of anticonvulsant drugs on circulating total and free T4 was not exhibited by the non-inducing sodium valproate. These data support the influence of enzyme induction as a likely mechanism for reduced thyroxine concentrations in treated epileptic patients.
Anticonvulsants↗
A double-blind comparison of conventional and controlled-release carbamazepine in healthy subjects.
1. Eight healthy subjects took part in a balanced, double-blind, crossover comparison of conventional carbamazepine (Tegretol, Ciba-Geigy Ltd, CBZ-C) and a novel controlled-release formulation (Tegretol CR Divitabs, Ciba-Geigy Ltd; CBZ-CR). An initial single dose of either preparation was followed 1 week later by a 2 week course of 200 mg twice daily. 2. Following the single dose, CBZ-CR produced a concentration plateau from 6-56 h at 50-60% of the CBZ-CR peak. 3. After 2 weeks' treatment, CBZ daytime levels measured as area under the concentration-time curve over a dosage interval were 7% lower with CBZ-CR, but this difference was not statistically significant. 4. CBZ-CR showed less diurnal fluctuation (12%) of CBZ than CBZ-C (24%; P less than 0.025) with less rapid changes in concentration (P less than 0.02). 5. Diurnal fluctuation of free CBZ and of CBZ 10,11 epoxide, the active metabolite, did not differ significantly between the two preparations. 6. Auto-induction of CBZ metabolism resulted from the administration of both formulations. The mean elimination half-life was 23 h (CBZ-C) and 25 h (CBZ-CR) after dose 29 compared with a base-line value of 37 h (both P less than 0.02). Antipyrine metabolism was also induced to a similar extent in both legs of the study (P less than 0.01). 7. No significant alteration in psychomotor function was demonstrated with either preparation. 8. CBZ-CR fulfils the criteria for a controlled-release preparation with comparable apparent bioavailability to CBZ-C. Further pharmacokinetic and, more importantly, pharmacodynamic studies are required in epileptic patients to confirm a clinical advantage over the currently available formulation.
Adult↗
Nifedipine for epilepsy? A pilot study.
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Adult↗
Microvascular disease and limited joint mobility in diabetes. A comparison of fibrinolysis and prostacyclin in diabetes and systemic sclerosis.
The pathogenesis of Limited Joint Mobility (LJM) in diabetes is unknown, but the abnormality is said to be associated with an increased incidence of microangiopathy. To examine the possibility that LJM may be a manifestation of microvascular disease, fibrinolysis and blood prostacyclin metabolites were measured in diabetic patients with and without LJM, and compared with patients who have systemic sclerosis (PSS). The concentrations of plasma fibrinogen (p less than 0.01) and Plasminogen Activator Activity (PAA) (p less than 0.02) were increased in both diabetic groups, compared with non-diabetic controls, and were of similar magnitude to the changes observed in PSS. Antithrombin III (AT III) activity was significantly lower in diabetic patients with LJM than in those without LJM, but not significantly different from controls. Prostacyclin concentrations were raised in PSS patients compared to controls (p less than 0.02) but were not raised in diabetic subjects. Thus abnormal fibrinolysis was demonstrated in diabetic patients compared to non-diabetic controls, and prostacyclin concentrations in diabetics were lower than in PSS patients. The diabetic patients with LJM had lower AT III activity than diabetics without LJM, but overall a convincing difference between the two groups of diabetics was not proven. No sure inferences could be drawn on the vascular aetiology of LJM, while the impaired prostacyclin activity might contribute to the development of diabetic microangiopathy.
Adult↗
Concentration-effect relationships with carbamazepine and its epoxide on psychomotor and cognitive function in epileptic patients.
A battery of psychometric tests was administered to 85 patients with epilepsy, of whom 26 were untreated, 40 received carbamazepine monotherapy and 19 took carbamazepine with another anticonvulsant. Carbamazepine alone had little effect on performance, but carbamazepine polypharmacy produced significant impairment. Increasing concentrations of carbamazepine (four tests) and its active metabolite, carbamazepine 10,11 epoxide (seven tests), correlated with decreasing performance in the monotherapy patients.
Adult↗
Psychomotor impairment and anticonvulsant therapy in adult epileptic patients.
Using a battery of simple tests, psychomotor performance was assessed in 11 healthy subjects, 14 untreated epileptic patients and 66 epileptics on chronic anticonvulsant medication. Significant differences were found between controls and untreated patients for choice reaction time, card sorting and Simple Simon memory game. Treated patients performed less well than both untreated epileptics and controls in choice reaction time (p less than 0.05; p less than 0.001), card sorting (p less than 0.01; p less than 0.001), Simple Simon (p less than 0.05; p less than 0.001) and finger tapping (p less than 0.05; p less than 0.001). Patients with centrencephalic epilepsy were slower than those with discrete focal EEG abnormalities in reaction time and card sorting. Patients receiving treatment with carbamazepine, phenytoin or sodium valproate alone all performed similarly to each other and to those patients taking anticonvulsant polypharmacy. Monotherapy patients with potentially "toxic" plasma anticonvulsant concentrations did no worse than those within or below the "therapeutic" range. Both the disease and its treatment reduce psychomotor performance. All major anticonvulsants appear to cause a similar degree of impairment across a wide range of concentrations. The effect of chronic anticonvulsant medication on "quality of life" should not be neglected in the pursuit of perfect seizure control.
Adolescent↗