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A 15 year old Oldenburger gelding was treated during 3 weeks for laminitis with the anticoagulant phenprocoumone (27 mg orally, once daily) and concurrent administration of phenylbutazone (2-4 g orally, twice daily). After this treatment the animal was presented to the Equine Clinic University of Zurich with a history of acute colic and advanced symptoms of shock. On the basis of the clinical signs and laboratory values, a diagnosis of combined drug induced coagulopathy was made. The horse was treated with the antidote Vitamine-K1 (0.5 mg/kg, subcutaneously). Eventually, the general condition of the animal worsened and it was therefore euthanized. Necropsy revealed profound, multifocal hemorrhagic diathesis of the serosal surface of the viscera, as well as bleeding into the visceral cavities. This case shows that concurrent administration of phenprocoumone and phenylbutazone may lead to drug interactions that increase the anticoagulation effect of the coumarine-derivative. Simultaneous use of coumarine-derivatives and phenylbutazone is therefore contraindicated due to the higher risk of bleeding. A reasonable treatment of horses with anticoagulants requires regular monitoring with constant evaluation of coagulation status and special attention to potential drug interactions.

Among the local complications following the intramuscular injection of therapeutic drugs, the syndrome of 'embolia cutis medicamentosa' deserves special attention. Shortly after the intramuscular injection, the patients notice severe pain and an erythematous discoloration of the skin at the injection site, followed by central demarcation and a sharply circumscribed skin necrosis with or without damage to peripheral nerves. We report about three patients, two of which had to be hospitalized. The drugs injected were combinations of analgesics of the phenylbutazone-type, corticosteroids, local anesthetics and cyanocobalamin. The observation that this severe complication may be associated with technically proper ventrogluteal injection of a wide array of therapeutic drugs shows that intramuscular injections require valid indications.

Methods: In an open clinical trial involving 20 patients, the question was investigated as to whether the administration of 3 x 300 mg mofebutazone daily resulted in any clinically relevant changes in blood sugar levels in diabetics treated with glibenclamide., Results: Fluctuations observed, both in mean and individual values, were within the range of those regularly seen in diabetics. This was shown by both weekly measurements and a comparison of daily profiles. A comparison of the daily blood sugar profile prior to and after three weeks of mofebutazone, revealed the following mean figures (+/- STD): prior to mofebutazone 12.30 hours 155.5 (+/- 23.2) mg/dl, 16.30 hours 147.2 (+/- 22.0) mg/dl; after 3 weeks of mofebutazone: 12.30 hours 162.7 (+/- 20.0) mg/dl, and 16.30 hours 151.7 (+/- 17.7) mg/dl. No side effects occurred, and no patient left the study prematurely. The laboratory parameters also studied showed no remarkable changes, either in mean values or in individual figures.

In 161 patients with rheumatoid arthritis a raised activity of alkaline serum phosphatase was found in 37.3% and identified as hepatic phosphatase by means of heat inactivation, and partly by determination of isoenzymes using the Polyacrylamidgel-electrophoresis. This relatively frequent finding may be explained as toxic hepatic damage due to antirheumatic therapy, and a drug-induced cholestasis. This is caused by several non steroidal antirheumatic drugs, especially upon longer administration, or in higher dosage or both, may be acting as potential hepatotoxic. Therefore, the control of alkaline serum phosphatase and gamma-GT before and during the antirheumatic treatment is recommended.

Acute oliguric renal failure due to acute interstitial nephritis developed in a patient after treatment with phenylbutazone. The histological, immuno-histological and serological features in this case are compatible with the involvement of a delayed hypersensitivity reaction in the pathogenesis of this drug-induced interstitial nephritis. Other side effects of phenylbutazone on the kidney and the water and electrolyte metabolism are discussed.

A rare secondary effect of intramuscular injections is reported in three own observations: This embolia cutis medicamentosa has been relatively often found in former times as result of bismuthe and mercury injections during lues therapy and today is only occasionally found, especially after intramuscular injections of phenylbutazone-containing antirheumatics. The question is discussed whether this medicamental embolism is really due to an embolic occlusion of small skin arteries. The typical clinical picture of the infarct-resembling skin necrosis in livid skin area could also be explained by vessel necrosis or thrombosis in the site of injection itself.

The effects of phenobarbital and phenylbutazone on hormonal contraception of clinically intact women were studied for the purpose of obtaining information on consequences of medicamentous enzyme induction. Disorders of bleeding were evaluated from four groups of probands who had received complementary doses of phenobarbital or phenylbutazone along with hormonal contraception, and findings were compared with data obtained from a control group. Occurrence of medicamentous enzyme induction was clinically reflected in an accumulation of functional bleeding disorders, depending on the hormonal contraceptive used as well as on the additionally administered drug. Conclusions were drawn for contraceptive practice.

A review is given on systemically applied drugs, which may cause vascular disturbances of the retina with possible irreversible involvment of the ocular function. Based upon personal observations and reports in the literature a series of drugs with such side effects is reported. In particular, besides retrolental fibroplasia and complications which can be induced by oestrogens, drugs are described, which on the basis of an allergic reaction may produce retinal haemorrhages or occlusions of retinal blood vessels.

The case of a 42-year-old man is reported, who on four occasions developed a hypokalaemic periodic paralysis after an intramuscular injection of "Ambene". The detailed examination of this patient shows, that it is the primary, autosomal dominant inherited form of hypokalaemic periodic paralysis, and not the secondary form, which is caused by a renal or gastrointestinal loss of potassium. Clinical and electrophysiological, as well as histopathological and electron microscopic findings are presented, showing the typical vacuolar myopathy with submicroscopic tubular structures. In the literature there is evidence for an increased sensitivity of the muscle membrane to insulin with an increased potassium-shift inside the cell in hypokalaemic periodic paralysis. "Ambene" is a combination, which contains amongst other substances dexamethasone and the local anaesthetic drug lidocain. In the present case the paresis was possibly caused by a combined effect of dexamethasone with a consequent hyperglycaemia and lidocain with a change in the excitability of the muscle membrane. The pathophysiological mechanism of hypokalaemic periodic paralysis is discussed in terms of the release by the combination of these two drugs. It has not previously been reported that "Ambene" can provoke a hypokalaemic periodic paralysis. This is a severe side effect because of the resulting cardiac and respiratory problems.

The drug-induced lupus erythematodes syndrome is a heterogeneous group of exogenically caused transitory autoimmunopathies . Essential knowledge has been got concerning the pathomechanism of the syndromes evoked by hydralazine, procainamide, diphenylhydantoin and Venopyronum . Though there are analogies to the systemic lupus erythematosus, we must take into consideration a diversity of diseases. Antibodies against histone have a certain diagnostic as well as pathogenetic relevance.

The rare clinical picture of the thrombocytopenia caused by drugs is described using own histories of diseases and data from literature. The questions of diagnostics and therapy are discussed. Despite the as a rule benign course it is referred to the fact to withold the noxa once diagnosed consequently from the patient for prevention of possible complications (cerebral haemorrhage).

Among the lesions of haematopoiesis conditioned by medicaments the lesions by non-steroidal antirheumatic drugs occupy the first place. They get their significance by the fact that they are not so infrequently irreparable and thus show an unfavourable prognosis. On principle in pathogenetic respect lesions by immunologic reactions which vastly do not depend on the dosage, are to be demarcated from the toxically conditioned side-effects which depend on dosage. Conditioned by drugs aplastic syndromes of the bone marrow are not in every case strongly depending on dosage. For this is to be assumed an individual, particular sensitivity of the haematopoietic stem cells (stem cell defect). Of the anti-rheumatic drugs used for the basic therapy chloroquine derivations, gold, D-penicillamine, immunosuppressives and levamisol may effect disturbances of the haematopoiesis, for which facts are examples are given. This concerns also the symptomatically acting antirheumatic drugs. An overestimation of rare side-effects of drugs should not block the application of certain medicaments, however, they should be given only in such a high dosage as it is necessary. In combinations of antirheumatic drugs every individual drug is considered as causative factor. Interactions are particularly be taken into consideration. Control programmes, particularly with certain laboratory parameters, give the early recognition of side-effects and render possible to avoid severe effects.

Modern medicine with its manifold therapeutic possibilites brings many side effects which might result in tissue damage. 8 cases of iatrogenic tissue damage seen over a period of 5 years are presented and discussed. Measures for correction and reconstruction are proposed.

In a previous open clinical trial with d-2-(6'-methoxy-2'-naphthyl)-propionic acid (naproxen) in 32 outpatients with osteoarthrosis, very good to good results were achieved in 6 patients, satisfactory in 12, fair in 5, and unsatisfactory in 9 patients. The severest side effect observed was a case of gastric bleeding in a female patient who had been previously treated with a drug containing phenylbutazone and prednisone. Since, furthermore, 6 out of 9 such patients who did not respond to therapy had to stop the durg prematurely because of minor side effects and since in another 6 there was a tendency to a reduction of the leucocyte count, we subsequently initiated a long-term efficacy and tolerance study in our department for chronic patients. This series comprised 15 patients, aged 66 to 86 years, with severe, partly immobilizing coxarthroses and gonarthroses. The length of treatment was 2 to 16 months (mean 10.5 months). During the first 3 months ESR determinations and complete blood counts were performed every two weeks, later at four-weekly intervals. The patients were questioned weekly as to the efficacy of the treatment and as to side effects. Neither changes of the laboratory data nor gastro-intestinal side effects were observed. In two patients -- one a female with multiple allergies -- treatment had to be stopped because of itching and exanthema, respectively. The analgesic effect of naproxen was evaluated as very good in 5 cases, good in 5, fair in 2, and unsatisfactory in 3 cases. In addition, we conducted another clinical trial in 15 outpatients with degenerative joint diseases (partly of the spinal column). Their age varied from 16 to 60 years. Naproxen was administered in daily doses from 500 to 750 mg for the duration of 6 to 12 weeks. In no case had treatment to be interrupted, nor was there any gastric intolerance or alteration of the blood count observed in this group. Clinical results were classified as satisfactory to good in 10 patients.

According to recent investigations two factors might play an essential role in the pathogenesis of rheumatoid arthritis (R.A.). Besides genetic components, i.e. the HLA-system and familial aggregation, the immune processes, mediating tissue inflammation and injury, are acknowledged as having established roles in the pathogenesis of R.A. The present report reemphasizes recent data concerning the autoimmunity and the immunologic network with trends of therapy in R.A. In view of the effectiveness of new nonsteroidal antiinflammatory drugs, a double-blind study of suxibuzon vs. indomethacin in 30 patients with active R.A. is described in detail. Both drugs were active and similar in their efficacy at 4 weeks as judged by clinical and laboratory measurements. No serious toxic side-effects were observed in both treatment regimens.

Animal experiments have shown that weekly intraarticular injections of various antiphlogistic/antirheumatic drugs into the knee joint induce progressive degenerative alterations in joint cartilage. The observed degenerations and destructions are most similar to the pathophysiology of osteoarthrosis in humans. By X-ray and macroscopic techniques the degenerative processes can be studied qualitatively and quantitatively. A decrease of joint space is a sensitive and early indicator of osteoarthrosis and showed that 10 weeks after intraarticular application of Ibuprofen, Phenylbutazone, Oxyphenbutazone, Flufenamic acid, Niflumic acid, Na-salicylate, Clofezone, Bumadizone and Dexamethasone the degenerative alterations in the injected knee joints were more severe than by applications of Chloroquine,D-penicillamine, Salicylamide and Indometacin. The degenerative effect on articular cartilage by the investigated drugs can be explained by their inhibitory potency on anabolic metabolism of connective tissue. The results of our animal experiments lead to the conclusion, that antiinflammatory drugs may also in man induce or accelerate degenerative joint diseases especially after long term treatment with high doses of these drugs.

The authors describe a simple non-crossover-blind test for the evaluation of subjective indices. A table for recording pains during the 14 days' study is described. The patient's satisfaction with the treatment and the number of days until withdrawal from the trial are recorded. The statistical procedure takes into consideration differences between the treatment groups and makes possible a valuable comparison with drugs tested in other clinical trials. The three dose schedules of antirheumatic treatment were tested on 122 patients and the results compared with those of 342 patients treated with the 6 other antirheumatic drugs (enteric-coated aspirin, paracetamol, indomethacin, flurbiprofen, mefenamic acid, and prednisolone) and those of 41 patients who received placebos. The results show that Safapryn (3,6 g aspirin + 3.0 g paracetamol daily) compared with 3.9 g enteric coated aspirin does not offer any advantage in its analgesic effect, although it gives rise to fewer side effects. Phenylbutazone (3000 mg) was almost as effective as 15 mg prednisolone daily. Between the effects of this dosage of phenylbutazone and other non-steroidal antirheumatic drugs, however, no significant difference could be detected. 50 mg phenylbutazone daily and placebo treatment could not be distinguished. The authors thank the Arthritis and Rheumatism Council for Research in Great Britain for its financial support. One of the authors (PL) was a Merck, Sharp, and Dohme Research Fellow and another one (PMB) received a Robins research scholarship.

Our previous experiments have shown that intraarticular injections of sodium iodoacetate or phenylbutazone into the knee joint of animals (hens) induce degeneration of the articular tissues. This method proved to be a useful model for experimental osteoarthrosis. After autopsy degenerative processes in the joint can be evaluated by macroscopical, histological and biochemical techniques, and show good correlations with osteoarthrosis in humans. To study the onset and progress of experimentally induced osteoarthrosis in living animals we developed a new X-ray method using special mammography-film (Kodak Definix Medical). By this technique also changes of the joint space can be measured quantitatively. Comparison between the degenerative lesions of cartilage as seen macroscopically during autopsy and the data obtained from the living animal by X-ray techniques show excellent correlations. By using X-ray mammography film in our studies of experimental model it is possible to observe the pathological alterations of the knee joint of the living animals and to investigate the effect of pharmacologically active compounds for the treatment of osteoarthrosis.

Morphologically identical liver damage may be caused by dihydralazine (Depressan, Nepresol) and propranolol (Obsidan, Dociton). Among 24 patients with clinical manifestations of drug-induced hepatitis associated with Depressan or Obsidan treatment, liver biopsies in 15 showed drug hepatitic changes with confluent necrosis. In five of these cases this finding was combined with cholangiolitis, in four there was a drug-induced hepatopathy resembling the picture of viral hepatitis. In 20 cases of Ketazon-induced liver damage the biopsy demonstrated toxic hepatosis with or without cholestasis, reactive hepatitis or cholangiolitis. A drug-related hepatitis with central lobular necrosis was observed in one patient with Ketazon-induced liver damage. In 28 patients a lymphocyte proliferation test was undertaken to confirm a causal relationship between the use of either Depressan, Obsidan or Ketazon and the morphologically demonstrated liver damage. The test was positive in 25 cases (18 with Depressan, 2 with Obsidan and 5 with Ketazon). In several uncertain cases, for example, exposure to both Depressan and Obsidan or to Ketazon and Rewodina, the morphologic picture could be attributed to a specific medication by the use of the lymphocyte proliferation test. The results of the lymphocyte proliferation test and the morphologic findings emphasize the role of cell-mediated immune reactions in the pathogenesis of liver damage from dihydralazine, propranolol, and ketophenylbutazone.

The influences of polymorphisms and pharmacokinetic defects of drug metabolism as causes of toxic drug reactions are presented. The different mechanisms of toxic side effects mediated by alterations of the metabolism and excretion of drugs are discussed.

A 59-year-old man developed a nephrotic syndrome and mild renal failure after treatment with phenylbutazone. Light microscope examination of a renal biopsy specimen showed minimal glomerular alterations, and electron microscopy showed diffuse fusion of epithelial cell foot processes without immune deposits. The interstitium revealed focal lymphocyte infiltrates identified as activated T-cells by immune histologic differentiation. The unusual combination of nephrotic syndrome with acute interstitial nephritis is a rare adverse reaction of nonsteroidal antiinflammatory drugs (NSAID). A disordered cell-mediated immunity could lead to interstitial infiltration of T-lymphocytes which, releasing lymphokines and a vascular permeability factor, cause the glomerular proteinuria. In addition, NSAID inhibition of prostaglandin synthesis may enhance production of these lymphocyte-derived substances. Since the nephrotic syndrome persisted 5 months after withdrawal of phenylbutazone, steroid therapy was initiated and 2 months later the renal insufficiency and proteinuria were resolved.

A review of the pharmacological induced taste disorders is given. Many patients complain only of a spontaneous metallic, bitter or salty sensation in their mouths. More serious is the development of a dissociated hypogeusia or even an ageusia. 7 cases with gustatory disturbances caused by orally given medicine are presented. The phenylbutazone, oxyphedrine, carbamazepine, Muskel-Trancopal comp. (Chlormezanon, Paracetamol) and Lioresal (baclofen) were accused to have caused a partial or complete loss of taste. After the treatment had been discontinued it took weeks or even months for a complete recovery.