Side effects of benoxaprofen.

A study was made of adverse dermatological reactions to the non-steroidal anti-inflammatory agent benoxaprofen. Photosensitivity was seen in several patients, confined to wavelengths less than 340 nm. Other cutaneous side effects were erythema multiforme, the Stevens-Johnson syndrome, milia, and onycholysis. One case of pancytopenia and toxic epidermal necrolysis was reported. patients were not rechallenged with the drug, but these reactions appear to be true side effects of benoxaprofen.     

Adverse reactions to D-penicillamine after gold toxicity.

The incidence of adverse reactions to D-penicillamine in 155 patients with rheumatoid arthritis was analysed and compared with their history of adverse reactions to gold. Out of 125 patients who took only D-penicillamine, 45 developed side effects from the drug, whereas of 27 patients with a history of gold toxicity, 18 also reacted adversely to D-penicillamine. All patients who took D-penicillamine within six months after an adverse reaction to gold developed side effects from D-penicillamine. Fourteen patients developed similar adverse reactions to D-penicillamine and gold, and the interval between treatments in this group was significantly shorter (p less than 0.01) than in those who developed either differing adverse reactions to both drugs or no reaction to D-penicillamine after treatment with gold. An interval exceeding six months between treatment with gold and treatment with D-penicillamine in patients who have developed adverse reactions to gold apparently reduces the risk of adverse reactions to D-penicillamine.     

Double blind dose-response study of zidovudine in AIDS and advanced HIV infection. Nordic Medical Research Councils' HIV Therapy Group.

OBJECTIVE--To compare the efficacy and side effects of 400 mg, 800 mg, and 1200 mg zidovudine daily in patients with AIDS or advanced HIV infection. DESIGN--Randomised, double blind, parallel group multicentre study. SETTING--Hospital departments of infectious diseases and dermatology in Denmark, Sweden, Norway, Finland, and Iceland. SUBJECTS--474 patients: 126 (27%) with AIDS; 248 (52%) with HIV related symptoms; 100 (21%) with low CD4+ cell counts. INTERVENTIONS--Zidovudine 400 mg (160 patients), 800 mg (158), or 1200 mg (156) daily. All patients received one capsule from each of three bottles four times daily. MAIN OUTCOME MEASURES--Survival; incidence of new HIV related events; CD4+ cell count; quality of life; incidence of haematological side effects. RESULTS--460 (97%) of the 474 patients had not received zidovudine previously. The median follow up period was 19 months, during which the death rates in the three treatment groups were 23% (36/160 patients), 23% (36/158), and 19% (30/156) respectively (p = 0.49; log rank test). One year after the trial was terminated the death rates were 38% (61/160), 41% (64/158), and 44% (68/156) respectively (p = 0.54). There was no significant difference between the groups in time to a new AIDS defining event or death, average number of events per patient, decline in CD4+ cell counts, wellbeing (visual analogue scale), or Karnofsky score. Zidovudine was withdrawn in 132 (28%) patients, mainly because of side effects (71 cases; 15%). The incidences of anaemia and leucopenia, time to first dose reduction, and numbers of patients withdrawn were all dose related. CONCLUSION--Zidovudine should be limited to 400-600 mg daily in patients with AIDS or advanced HIV infection.     

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.     

Incidence of metal sensitivity in patients with total joint replacements.

Sensitivity to chromium, cobalt, nickel, molybdenum, vanadium, and titanium was studied by patch tests in 50 patients who had received total joint replacements. Nineteen (38%) were sensitive to one or more of the metals. In 23 patients non-traumatic failure of the prosthesis had occurred, and 15 of these patients were sensitive to metal. Out of 27 patients with no evidence of prosthesis loosening, four were sensitive to nickel and cobalt or nickel only. Dermatological reactions occurred in 13 patients after surgery; in only eight, however, was there evidence of metal sensitivity. These findings indicate that metal-on-metal total joint replacements may sensitise the patient to metals contained in the prosthesis. Although there is a high incidence of prosthesis failure among metal-sensitive patients it remains uncertain whether the loosening causes the sensitisation or vice versa.     

Incidences of fatal postoperative pulmonary embolism after prophylaxis with dextran 70 and low-dose heparin: an international multicentre study.

A total of 4352 patients were admitted to a prospective'' randomised multicentre trial comparing the prophylactic efficacy of dextran 70 and low-dose heparin against fatal pulmonary embolism after elective operations for general, orthopaedic, urological, and gynaecological conditions. Out of 3984 patients correctly admitted, 1993 were allocated to receive dextran 70 and 1991 to receive low-dose heparin. Withdrawal of prophylaxis because of bleeding or technical difficulties occurred more often in the heparin group, but allergic reactions were more common in the dextran group. Of the 75 patients who died within 30 days after operation, 38 had been given dextran and 37 low-dose heparin. Necropsy was performed in 33 and 32 of these cases respectively. In six patients in each group pulmonary embolism was the sole or a contributory cause of death. Of these, five patients in the dextran group and two in the heparin group had received a full course of prophylaxis. There was no statistically significant difference between the two treatment groups in the incidence of fatal pulmonary embolism after a full course of prophylaxis.     

A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): a multicentre unblinded randomised clinical trial.

OBJECTIVE: To compare aspirin with anticoagulation with regard to risk of cardiac death and reinfarction in patients who received anistreplase thrombolysis for myocardial infarction. DESIGN: A multicentre unblinded randomised clinical trial. SETTING: 38 hospitals in six countries. SUBJECTS: 1036 patients who had been treated with anistreplase for myocardial infarction were randomly assigned to either aspirin (150 mg daily) or anticoagulation (intravenous heparin followed by warfarin or other oral anticoagulant). The trial was stopped earlier than originally intended because of the slowing rate of recruitment. MAIN OUTCOME MEASURE: Cardiac death or recurrent myocardial infarction at 30 days. RESULTS: After 30 days cardiac death or reinfarction, occurred in 11.0% (57/517) of the patients treated with anticoagulation and 11.2% (58/519) of the patients treated with aspirin (odds ratio 1.02, 95% confidence interval 0.69 to 1.50, P = 0.92). Corresponding findings at three months were 13.2% (68/517) and 12.1% (63/519) (0.91, 0.63 to 1.32, P = 0.67). Patients receiving anticoagulation were more likely than patients receiving aspirin to have had severe bleeding or a stroke by three months (3.9% v 1.7% (0.44, 0.20 to 0.97, P = 0.04)). CONCLUSION: No evidence of a difference in the incidence of cardiac events was found between the two treatment groups, though the trial is too small to claim treatment equivalence confidently. A higher incidence of severe bleeding events and strokes was detected in the group receiving anticoagulation, suggesting that aspirin may be the drug of choice for most patients in this context.     

Amiodarone for refractory cardiac arrhythmias: 10-year study.

Over a 10-year period 130 patients with drug-resistant cardiac arrhythmias associated mainly with coronary artery disease and its complications were treated with amiodarone. The drug controlled all the tachyarrhythmias associated with the Wolff-Parkinson-White syndrome, 95% of the ventricular arrhythmias, including recurrent ventricular tachycardia and fibrillation, and 92% of the supraventricular arrhythmias. The maximum duration of therapy was 111 months and the mean 34 months. Side effects occurred in 34% of the patients, and there was one withdrawal from therapy per 15.3 patient-years of treatment. The commonest cause of withdrawal was nausea, which was significantly related (p less than 0.01) to a drug interaction with digoxin and diuretics. Reversible neurologic complications occurred in eight patients (6%), and acute myositis was recognized for the first time. Pulmonary infiltration developed in four patients (3%), who were receiving 600 mg of amiodarone per day. The rates of side effects and of withdrawal from therapy differed significantly between the patients whose maintenance doses were 600 and 200 mg/d, at 59% v. 6% (p less than 0.01) and 32% v. 0% (p less than 0.05) respectively. Thus, amiodarone is a very effective antiarrhythmic that can be administered over long periods with acceptable rates of side effects and withdrawal provided the minimal effective dose is used; 400 mg/d or less is desirable.     

High incidence of vincristine-induced neuropathy in lymphomas.

The incidence of vincristine-induced neuropathy was studied in 60 unselected patients, of whom 23 had lymphoma and 37 had other malignant disease. All were treated with vincristine combined with other cytotoxic agents. Fourteen of the patients with lymphoma (61%) developed neuropathy compared with five patients with leukaemia or non-lymphoid cancer (14%), even though all patients received comparable doses of vincristine. The difference between the two groups in the incidence of neuropathy was highly significant. Of the patients who developed neuropathy, 17 did so within the first three months of treatment and seven in the first month. Patients with lymphoma who are receiving vincristine should be observed carfully for symptoms and signs of neuropathy. Vincristine should be withdrawn if progressive neurotoxicity develops.     

Timing, conditions, and complications of post-operative conception and pregnancy in female renal transplant recipients

The aim of this study was to explore the timing, conditions, and complications of post-operative conception and pregnancy among female renal transplant recipients in China. A cohort of 25 female renal transplant recipients who subsequently had successful pregnancies was randomly selected from eight organ transplantation centers in China. In this cohort, there were 38 post-transplant conceptions and 25 live births. The effects of conception and pregnancy on renal function as well as any effects of transplantation on delivery, prematurity, and maternal and infant health were investigated. Out of 38 conceptions after transplantation, seven ended in spontaneous abortion, six in artificial abortion, and 25 in single births, seven of which were premature (28%). The growth and development of all of the infants were normal. All the 25 received artificial (formula) feeding. Six patients had to return to hemodialysis therapy at 1–41 months after conception due to reduced function of the transplanted kidney. It appears best for female renal transplant recipients to wait at least for 2 years post-transplant before pregnancy. We found no significant effect on fetal growth and development. The incidence of premature births among female renal transplant recipients was high which might have an effect on transplant renal function and maternal health. Breast feeding is not considered suitable for these patients and was therefore not studied.     

Diazepam: A Preliminary Study of its Effects on Patients with Athetoid Cerebral Palsy

Diazepam was administered to seven severely affected athetoid children for a period of two to three months to determine whether beneficial effects could be demonstrated from its use. All patients were started on a daily dose of 2.5 mg. and the dose was increased as tolerated. The patients were assessed by a neurologist, an occupational therapist, a physiotherapist and a speech therapist before and after the trial.The dose of diazepam cannot be determined in advance. The optimum dose must be established by trial in each individual patient. No beneficial effects were noted in four of these children. One of those who showed improvement became significantly worse when the drug was withdrawn and it was necessary to reinstitute the drug. The response in any individual patient is unpredictable. The most significant side effect was drowsiness.     

Sulphasalazine retention enemas in ulcerative colitis: a double-blind trial.

Thirty-four patients with ulcerative colitis completed a double-blind assessment comparing the efficacy of two weeks of treatment with nightly retention enemas containing 3 g sulphasalazine or placebo. Symptom grading, sigmoidoscopic appearance, rectal biopsy specimens, and diary records were used to assess benefit and side effects. The active drug conferred significant benefit compared with placebo as shown by several criteria, but this benefit was confined to patients not already taking sulphasalazine by mouth. Overall assessment showed improvement in 11 of the 16 patients (70%) given the active treatment but in only two of the 18 (11%) given placebo. No side effects attributable to the drug were observed, even in patients previously intolerant to oral preparations. The logical therapeutic role of sulphasalazine enemas in ulcerative colitis would appear to be in patients who experience side effects such as nausea, abdominal discomfort, or headaches when taking the drug by mouth.     

Improvement in prognosis of myocardial infarction by long-term beta-adrenoreceptor blockade using practolol. A multicentre international study.

In a large-scale double-blind controlled trial of practolol (200 mg twice daily) in the long-term prophylactic treatment of 3038 patients recovering from acute myocardial infarction treatment was started one to four weeks after the acute attack. The trial was originally planned to include 4000 patients treated for at least a year but had to be terminated prematurely because of the serious oculocutaneous and peritoneal reactions reported elsewhere. Nevertheless, important findings, probably applicable to other beta-adrenoreceptor antagonists, have emerged in relation to mortality and morbidity. (1) The practolol-treated group showed a significant reduction in overall mortality and in sudden deaths; (2) there was a highly significant reduction in "all cardiac events"; (3) the reduction in overall mortality was virtually confined to patients whose original pre-entry infarcts were sited anteriorly; (4) the protective effect of practolol was most evident in those patients with pre-entry anterior infarcts whose blood pressures at entry were below the mean for the trial as a whole; (5) there were highly significant group differences in favour of the drug relating to the incidence of angina pectoris and cardiac arrhythmias, and to the numbers of patients who had to be withdrawn from the trial because of these conditions; (6) significantly more patients were withdrawn from the treatment group because of suspected adverse reactions. It is concluded that practolol used in the long-term treatment of patients who have survived the acute phase of myocardial infarction reduces the death rate when the original infarct is sited anteriorly. It is postulated that the favourable results of the trial were due to beta-adrenoreceptor blockade rather than to some other property specific to practolol itself. Since practolol produces severe side effects in long-term use it is recommended that an alternative beta-adrenoreceptor blocking agent should be used.     

Low dosage progestagen as an oral contraceptive: a clinical study

A low dose of an oral progestagen (norethindrone 0.35 mg. daily) was used as a contraceptive agent in a group of 70 women. The average period of use was 16.7 months; it was over two years in 21 subjects. Eight patients withdrew from the trial because of excessive or irregular bleeding. The incidence of side effects was lower than with the combined type of contraceptive preparations. Of the six pregnancies that occurred, only two could be attributed to failure of the method.     

Optimum duration of antithyroid drug treatment determined by assay of thyroid stimulating antibody in patients with Graves' disease.

OBJECTIVE--To determine the optimal duration of antithyroid drug treatment by monitoring serum thyroid stimulating antibody values in patients with Graves'' disease. DESIGN--Prospective longitudinal trial of patients with Graves'' disease followed up for 24 months after withdrawal of treatment. SETTING--Tertiary referral centre. PATIENTS--A total of 64 consecutive patients with untreated Graves'' disease, eight of whom were subsequently excluded. Fifty six patients completed the study. INTERVENTIONS--All patients were treated initially with carbimazole 40 mg, then with decreasing doses that maintained a euthyroid state. Treatment was scheduled to continue for 18 months but was withdrawn earlier if serum thyroid stimulating antibody became undetectable. END POINT--Serum values of thyroid stimulating antibody (assayed by stimulation of human thyroid cells in vitro) and thyroid hormones and thyroid state every three months during treatment and afterwards every six months for 24 months. MEASUREMENTS AND MAIN RESULTS--In 44 patients serum thyroid stimulating antibody became undetectable during treatment and treatment was withdrawn (median duration of treatment nine months, range 3-18 months). In 12 patients the antibody could be detected during 18 months of treatment. Among the first group of 44 patients initial values of the antibody before treatment were significantly lower than in the second group of 12 patients (median 225% (range 138-1236%) v 570% (250-1480%), p less than 0.001); the incidence of relapse was also lower (41% v 92%, p less than 0.001); and among those who did relapse the disease free interval after treatment was longer (median 12 months v 1 month, p less than 0.001). Moreover, the initial median serum values of thyroid stimulating antibodies were not related to the occurrence of relapse or remission as these did not differ between patients who did and did not have a relapse (median 267% (range 139-1480%) v 220% (range 138-1236%). CONCLUSION--Monitoring of serum thyroid stimulating antibody was a good guide to the duration of treatment as it allowed the treatment period to be considerably shortened in a large group of patients with no loss of efficiency.     

Potentially Serious Side Effects of High-dose Twice-weekly Rifampicin

Daily rifampicin in a single dose of 600 mg, combined with other drugs, usually streptomycin and isoniazid, was given to 49 patients for three months. It was planned to continue for another 15 months with twice-weekly rifampicin 1,200 mg plus isoniazid 900 mg, but the high incidence of side effects led to cessation of the intermittent regimen when only two patients had completed 18 months.Though there was no serious problem with daily treatment 11 patients (22%) were unable to continue rifampicin on the intermittent regimen. In 8 (16%) a pyrexial syndrome occurred. In one of these patients there was also temporary renal failure, and in another precipitous thrombocytopenia led to epistaxis and bleeding into the tongue and lips. Symptomless thrombocytopenia developed in two other patients, making three cases (6%) of thrombocytopenia in all.In 16 (33%) of the 49 patients antibodies to rifampicin were detected in the blood. Side effects occurred in 9 (56%) of these, including the three developing thrombocytopenia, but in only 2 (6%) of the 33 patients with no antibodies detected. This association of toxic reactions with antibodies is highly significant (P<0·001).     

Nifedipine and atenolol singly and combined for treatment of essential hypertension: comparative multicentre study in general practice in the United Kingdom

A randomised double blind parallel group study was performed to compare the efficacy and acceptability of slow release nifedipine (maximum dose 40 mg twice a day) with those of atenolol (maximum dose 100 mg once a day) as single agents for the treatment of essential hypertension. Of 410 patients recruited almost exclusively from general practices in 22 centres in the United Kingdom 210 received nifedipine and 200 atenolol. Both drugs significantly reduced blood pressure, and control—a reduction of the diastolic pressure to less than 95 mm Hg—was obtained in about 65% of patients. Those who received nifedipine had more pronounced reductions in systolic pressure than those who received atenolol. One hundred and forty nine patients who failed to respond adequately to either atenolol or nifedipine in low doses were given both drugs once daily for eight weeks in a fixed combination capsule that contained atenolol 50 mg and nifedipine 20 mg. All patients showed further reductions in blood pressure, although those who were taking β atenolol before the combination capsule had more pronounced reductions in systolic pressures. Twenty six patients (12%) were withdrawn because of adverse effects while taking nifedipine compared with 19 (10%) taking atenolol. Flushing and oedema were more common after the calcium antagonist, whereas diarrhoea and dyspepsia were more common after atenolol. The frequencies of headaches, dizziness, fatigue, and dyspnoea were equally distributed between the two groups. When the fixed combination capsule was taken side effects such as flushing and oedema continued.Nifedipine was more effective than atenolol in lowering systolic blood pressure, although neither drug used alone controlled the pressure of more than two thirds of the patients studied. When used in a fixed combination slightly better control of blood pressure was achieved with a lower dose of each drug.     

Effects of sodium valproate in 100 children with special reference to weight.

Excessive weight gain occurred in a patient who was taking sodium valproate and phenytoin. The sodium valproate was therefore withdrawn but the rapid weight loss that ensued led to phenytoin intoxication. Hence a retrospective analysis was conducted of 100 children with epilepsy treated with sodium valproate. Fit control improved in 77 and was best in children with generalised epilepsy. None of the reported severe side effects, such as acute liver disease and pancreatitis, were encountered. Milder but troublesome side effects, however, occurred in 65 patients. The commonest was increased weight gain, which occurred in 44 cases. Others were transient gastrointestinal disturbances (20), lassitude (nine), transient hair loss (six), transient enuresis (seven), and aggressive behaviour (four).     

Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs.

OBJECTIVE--To estimate the prevalence of important side effects in patients with malignant disease who were receiving high doses of morphine as part of their palliative treatment. DESIGN--Data on patients were collected over 12 months. SETTING--Two palliative care units in Western Australia. PATIENTS--19 Patients with malignant disease who were receiving morphine either subcutaneously or orally as the main analgesic. 10 Patients receiving a total daily dose of morphine of at least 500 mg orally or 250 mg parenterally were enrolled in the study. The other 9 patients were enrolled after an important problem thought to be related to the morphine had been identified. All of the patients were taking drugs to supplement the treatment. INTERVENTIONS--The dose of morphine or route of administration, or both, was changed in three patients. MAIN OUTCOME MEASURE--Determination of the prevalence of side effects in the patients. Assessment of the relation of any side effects with the supplemental drugs taken by the patients. MAIN RESULTS--Plasma morphine and electrolyte concentrations were measured and a full history taken for each patient. Thirteen of the 19 patients had an important side effect; 12 of them had myoclonus and one had hyperalgesia of the skin. Plasma morphine concentrations were similar in patients with and without myoclonus, ranging from 158 to 3465 nmol/l and 39 to 2821 nmol/l respectively. Eight of the patients with side effects were taking an antipsychotic drug concurrently compared with none of those without side effects. A greater proportion of patients with side effects were taking the antinauseant drug thiethylperazine (6/13 v 2/6) and at least one non-steroidal anti-inflammatory drug (10/13 v 2/6), whereas a smaller proportion were taking a glucocorticosteroid (3/13 v 4/6). The estimated prevalence of important side effects in the total population of patients receiving palliative treatment in the two units was 2.7-3.6%. CONCLUSIONS--Myoclonus as a side effect of treatment with morphine is more likely to occur in patients taking antidepressant or antipsychotic drugs as antiemetics or as adjuvant agents or non-steroidal anti-inflammatory drugs for additional analgesia. If a patient develops myoclonus the best approach may be to change the supplemental treatment.     

Neurological effects of recombinant human interferon.

Ten women with advanced locally recurrent breast cancer who had failed to respond to radiation and hormonal and cytotoxic agents were given up to 12 weeks of recombinant leucocyte interferon 20 X 10(6) U/m2 daily or 50 X 10(6) U/m2 three times a week. Within one hour of administration influenza-like symptoms began, which one week later were superseded by lethargy, anorexia, and nausea, with a consequent loss of weight in most patients. Other side effects included profound somnolence, confusion, paraesthesia, and (in one patient) signs of an upper motor neurone lesion in the legs. All these effects together with increased slow wave activity in electroencephalograms from all patients during treatment disappeared when interferon was withdrawn and did not recur on reintroducing the drug at a lower dosage. Studies are continuing to determine the mechanisms of these effects.