Hepatic toxicity of antiepileptic drugs: a review.

Hepatic toxicity of antiepileptic drugs has been well recognized for many years. Despite the increasing awareness of chronic toxicity of antiepileptic drugs, this aspect has remained of limited importance. Since the introduction of valproate, this situation has changed fundamentally. Following a general introduction to the classification and symptomatology of drug-induced hepatic toxicity, a detailed description of hepatic toxicity caused by phenytoin, carbamazepine, and valproate is presented, including classification, symptomatology and histological features. Hepatic toxicity caused by all three drugs may be classified as idiosyncratic reactions. However, whereas toxic reactions following phenytoin and carbamazepine are characterised by a rather short duration of exposure before symptoms occur with accompanying clinical features of hypersensitivity, valproate-induced hepatic toxicity exhibits no signs of hypersensitivity and often occurs following prolonged exposure, speaking in favor of a metabolic aberration as the underlying cause. Hypotheses explaining the mechanisms involved in this phenomenon are reviewed. Guidelines for averting valproate-induced hepatic toxicity are presented.

Serum aminoterminal type III procollagen peptide. Relation to biosynthesis of collagen type III in experimentally induced granulation tissue in rats.

Serum aminoterminal type III procollagen peptide was measured in rats during the development of granulation tissue induced by subcutaneous implantation of viscose cellulose sponges. Active collagen type III synthesis in granulation tissue during the first three weeks was accompanied by an increase in serum propeptide level. A positive correlation was observed between the increase in serum propeptide level on the one hand and the increase in granulation tissue collagen type III content and the in vitro formation of tissue 3H-hydroxyproline on the other hand. In some animals the serum propeptide level remained low, despite biochemical signs of collagen synthesis, indicating variations in the release into serum and/or the metabolism of circulating propeptide. The increase in propeptide antigen concentration was mainly due to an elevated content of material with molecular weight equal to or twice that of the propeptide. A minor fraction of the propeptide remained attached to the interstitial collagen fibres in the granulation tissue. The correlation between the serum propeptide level and the biosynthesis of collagen at the site of the focal fibroproliferative process suggests that the serum propeptide level may be a valuable indicator of fibrogenesis and thereby of disease activity in fibrotic conditions.

Plasma histidine-rich glycoprotein and plasminogen in patients with liver disease.

Histidine-rich glycoprotein (HRG) has been reported to be a fibrinolysis regulating protein due to its capacity to bind to the high affinity lysine binding sites of plasminogen. Using immunological methods we have measured the concentrations in plasma of HRG and total plasminogen and calculated the amounts of plasminogen not bound to HRG (free plasminogen) in 28 patients with moderate to severe liver disease. All three parametres showed wide individual variations, but with decreasing functional capacity of the liver the individual levels of plasminogen were reduced earlier than those of HRG leading to decreased amounts of free plasminogen. Simultaneous determinations of HRG and total plasminogen combined with a calculation of free plasminogen might yield valuable information when evaluating patients for the availability of plasminogen.

Connective tissue metabolites in serum as markers of disease activity in patients with rheumatoid arthritis.

The serum levels of aminoterminal type III procollagen peptide (S-PIIINP), immunoreactive prolyl 4-hydroxylase protein (S-IRPH), 7S domain of collagen type IV (S-Col IV, 7S), and fragment P1 of laminin (S-Lam), which are associated with the metabolism of extracellular interstitial collagens and basement membranes, were measured sequentially for two years in 14 rheumatoid arthritis (RA) patients undergoing disease modifying antirheumatic drug treatment. Elevated S-PIIINP, S-IRPH, and S-Col IV, 7S levels were demonstrated in active RA. In active disease the metabolites showed some correlation with clinical and serological signs of disease activity. A high average synovial fluid/serum concentration ratio of PIIINP and of Col IV, 7S supports the concept that the increased serum levels of PIIINP and Col IV, 7S originated from the diseased joints. After 2 years of treatment a decline was observed in S-PIIINP and S-Col IV, 7S in treatment responders. However, the median levels of S-PIIINP and S-IRPH were still above the upper limit of normal, suggesting smouldering, subclinical inflammatory processes. S-Lam remained within the normal range in active and inactive disease.

Serum aminoterminal type III procollagen peptide in inflammatory and degenerative rheumatic disorders.

Measurement of the aminoterminal type III procollagen peptide in serum has been suggested as a marker of the biosynthesis of collagen type III, a major connective tissue component in repair processes. In the present study the propeptide level correlated with the inflammatory synovial mass in rheumatoid arthritis and osteoarthritis. This implies that the propeptide level reflects the collagen type III synthesis occurring in the synovial repair processes, whether they were caused by inflammatory or degenerative rheumatic disorders. Physical activity did not enhance the transition of the propeptide from the synovial fluid or the inflamed synovial membrane to the blood. Normal serum propeptide values were observed in most patients with ankylosing spondylitis and degenerative diseases of the spine. This may reflect the lower amount of inflammatory tissue in these diseases and hence the sensitivity of the assays.

[3 cases of visceral leishmaniasis, one in a HIV-positive man]. / Tre tilfaelde af visceral leishmaniasis: det ene hos en HIV-positiv mand.

Three cases of visceral leishmaniasis (kala-azar) are presented. One of these was in a 43-year-old patient with AIDS who was infected in Southern Spain. Another was in a man aged 25 years infected in West Africa. These cases are the first two adults to be reported in Denmark. The third case was an 18 month old previously healthy boy, infected in Southern Spain. The symptomtology, diagnosis and treatment of the disease are discussed and it is stressed that serological diagnostic tests have limited value in HIV positive patients.

[AIDS in Denmark. 1. Opportunistic infections and malignant diseases. Danish Study Group for HIV infection]. / AIDS i Danmark. 1. Opportunistiske infektioner og maligne sygdomme. Danish Study Group for HIV Infection.

To examine the distribution of AIDS-defining illnesses among Danish AIDS patients, data on 687 AIDS patients diagnosed in the period from 1980 to 1990 (93% of all reported cases in the period) were collected. The most frequent AIDS-defining illness was Pneumocystis carinii pneumonia followed by candida oesophagitis and Kaposis sarcoma. The proportion of homo/bisexual men presenting with Kaposis sarcoma as the initial AIDS-defining illness declined over time. Patients with extrapulmonary tuberculosis had higher CD4 cell counts than patients presenting with other illnesses. Cytomegalovirus chorioretinitis and atypical mycobacteriosis were seen more frequently after the time of the AIDS diagnosis, and a low CD4 cell count at time of the AIDS diagnosis was a significant predictor for the development of these opportunistic infections during follow-up. Danish AIDS patients present with a wide spectrum of HIV-related illnesses, reflecting their exposure to opportunistic microorganisms and the degree of immune deficiency. The pattern of HIV-related illnesses is changing over time, and therefore continuous surveillance is needed to optimize therapeutic and prophylactic regimens.

[AIDS in Denmark. 2. Survival after the diagnosis of AIDS. Danish Study Group for HIV infection]. / AIDS i Danmark. 2. Overlevelse efter AIDS-diagnosen. Danish Study Group for HIV Infection.

The survival pattern was studied for 687 Danish AIDS patients (93% of notified cases in the study period) who were diagnosed with AIDS during the period from 1980 to 1990. The median survival was 17 months. Factors significantly associated with a shortened survival were transfusion-acquired HIV infection, age > 40 years, year of diagnosis before 1987, and the presence of either disseminated infection with Mycobacterium avium-complex, Cytomegalovirus chorioretinitis or malignant lymphoma at time of the AIDS diagnosis. There was also a significant association between survival and CD4 cell count at time of AIDS diagnosis. Patients who had CD4 cell counts above 200 x 10(6)/l had twice as long a survival as patients who had CD4 cell counts less than 50 x 10(6)/l. The prognosis of Danish AIDS patients remains poor. The most important determinant of survival time appears to be the degree of immune deficiency at time of diagnosis.

Valproate: an updated review.

Valproate in all its aspects is comprehensively surveyed. Previous reviews covering various aspects such as mechanism of action, clinical pharmacology, clinical efficacy in epilepsy, febrile convulsions and other neurological disorders, side effects, teratogenicity and intoxications are discussed and updated (161 references).

Platelet aggregation and release of ATP in patients with hepatic cirrhosis.

The purpose of this study was to assess the platelet aggregation and releasable platelet ATP in patients with alcoholic cirrhosis (n = 10) and primary biliary cirrhosis (n = 10). In patients with liver disease a significant decrease was found in both adenosine diphosphate-induced aggregation (P less than 0.01) and collagen-induced aggregation (P less than 0.001) compared with that of controls, but there was no significant difference between the two groups of patients. Patients with primary biliary cirrhosis release smaller amounts of ATP than patients with alcoholic cirrhosis, and compared with the controls there was a significant (P less than 0.001) decrease in the releasable ATP in the patient groups. These results suggest that platelets are damaged during an intravascular activation (loss of granules), which gives rise to their subsequent hypo-function when tested in vitro.

Splanchnic and renal extraction of circulating hyaluronan in patients with alcoholic liver disease.

Splanchnic and renal extraction of hyaluronan was determined in patients with alcoholic cirrhosis (n = 9), non-cirrhotic alcoholic liver disease (n = 5), and controls without liver disease (n = 19) in the supine fasting condition. Arterial plasma concentration of hyaluronan was significantly increased in patients with cirrhosis (mean 480 micrograms/l) as compared to non-cirrhotic patients (29 micrograms/l, P less than 0.001) and controls (25 micrograms/l, P less than 0.001), whereas no difference was present between the two last-mentioned groups. In patients with liver disease, circulating hyaluronan was inversely correlated to indocyanine green clearance (r = -0.85, P less than 0.001) and to galactose elimination capacity (r = -0.62, P less than 0.02), but positively correlated to portal pressure (determined as wedged-to-free hepatic vein pressure) (r = 0.92, P less than 0.001). Splanchnic extraction ratio (arterio-hepatic venous extraction ratio) had a mean value of 0.14 in patients with cirrhosis as compared to 0.36 in non-cirrhotic patients (P less than 0.05) and 0.34 in controls (P less than 0.025). Splanchnic hyaluronan extraction was not correlated to liver function tests or portal pressure. In patients with alcoholic liver disease no significant renal hyaluronan extraction was found as compared to an extraction ratio of 0.17 in controls (P less than 0.05). Our results suggest that the increased level of circulating endogenous hyaluronan found in patients with cirrhosis is caused by a combination of increased supply to and decreased extraction from plasma.

Controlled trials in epilepsy: a review.

A comprehensive review, evaluating 51 randomized double-blind controlled studies, covering different aspects of epileptology, is presented. Trials were grouped according to the investigated topic and for each group an attempt was made to derive an overall conclusion. The majority of studies investigated antiepileptic drug treatments. Other topics were: psychotropic effect of antiepileptic drugs, folic acid and vitamin D administration in epilepsy, and EEG investigations. A cross-sectional analysis of items such as designs, patient sampling principles, recording of effect parameters and side effects, concomitant treatments, and statistical evaluations demonstrated that cross-over designs, investigating fixed dosage schedules, were extensively used. Less than half of these studies included a washout period between treatments, complicating the interpretation of the obtained results. The vast majority of studies involved only chronic patients; and marked heterogeneity in patient selection with respect to age, seizure type, and mental status, and severity of epilepsy was observed. Classifications of seizures varied between the studies. The most prominent effect parameter was seizure frequency. The use of heterogeneous patient samples frequently necessitated equalization of widely different seizure types in order to perform statistical analyses. The mean duration of trials was 6 months, precluding evaluation of chronic toxicity. The majority of studies recorded side effects, but data collection was rather unsystematic and statistical evaluation was seldom applied. Most studies were add-on trials, and since concomitant treatment was frequently changed during the investigations, it was difficult to evaluate the influence of this variable. A correlation analysis across trials demonstrated, among other things, that the common assumption that short controlled trials provide too optimistic results, could not be substantiated. This survey provides no firm indication of which drug is more suitable for which seizure type.

Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study.

Studies investigating the influence of antiepileptic drugs on thyroid hormones usually have compared patients chronically treated with antiepileptic drugs to controls. To date, this type of designs has produced divergent results both with regard to individual drugs and individual thyroid hormones. The present study comprised 31 patients with newly diagnosed epilepsy, commencing treatment with either carbamazepine or valproate. T3, T4, FT4, FT3, rT3, TSH, T3 resin uptake and blood folic acid, were determined before and during antiepileptic monotherapy, thus making the patient his own control. During treatment with carbamazepine, a significant decrease in T4, FT4, FT3, rT3 and TBG was observed. Valproate caused a decrease in T4, FT4 and T3. Neither of the drugs caused any changes in blood folic acid concentrations or persistent increases in the TSH values. None of the patients developed overt symptoms of hypothyreoidism. Conceivable mechanisms underlying these hormonal changes are reviewed.

Serum procollagen III peptide in chronic myeloproliferative disorders.

Using a radioimmunoassay the serum concentration of the N-terminal propeptide of type III procollagen (P-III-P) was measured in 35 patients with chronic myeloproliferative disorders, including idiopathic myelofibrosis (n = 10), osteomyelosclerosis (n = 4), transitional myeloproliferative disorder (n = 5), polycythaemia vera (n = 10) and chronic myelogenous leukaemia (n = 6). The normal range in 35 healthy controls was 4.9-11.7 ng/ml. The serum concentration of P-III-P increased with increasing degrees of bone marrow reticulin fibrosis. By contrast, almost normal levels were detected in osteomyelosclerosis with an indolent clinical course, in which an excessive deposition of mature collagen fibres was found, representing mainly type I collagen. These observations indicate that the serum P-III-P level is positively correlated to the degree of bone marrow reticulin fibrosis, whereas levels are near normal in patients with osteomyelosclerosis and stable disease. Measurement of serum P-III-P may be a useful indicator of disease activity in myelofibrosing conditions.