Do beta-adrenergic blocking agents increase asthma exacerbation? A network meta-analysis of randomized controlled trials.

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.

An instructive example of a long-latency adverse drug reaction--sclerosing peritonitis due to practolol.

OBJECTIVE: By examination of the original Yellow Card data to determine the duration of the latent period of the sclerosing peritonitis which formed part of the oculomucocutaneous syndrome that was associated with practolol, the beta-adrenergic receptor blocking agent that was withdrawn from clinical usage in the UK in December 1975 in response to reports of the syndrome. METHOD: Relevant drug analysis prints (DAPs) for practolol were obtained from the Medicines and Healthcare Products Regulatory Agency (MHRA) and, by application to the Interim Committee on Yellow Card data, copies were obtained of the anonymised Yellow Card reports for all the 201 cases of sclerosing peritonitis that were reported in patients treated with practolol. These data were used to determine the latent period of this iatrogenic adverse drug reaction. RESULTS: It was shown that no other cause than practolol operated in all or a majority of the cases of sclerosing peritonitis and the suspected adverse reaction could properly be attributed to the drug. The latent period (the time period between the drug start date and the reaction start date) of the sclerosing peritonitis associated with practolol averaged 201 weeks (range 26-606 weeks; standard deviation 130 weeks). CONCLUSION: The latent period of the sclerosing peritonitis that formed part of the practolol oculomucocutaneous syndrome averaged about 4 years and had a range of from 0.5 to over 11.5 years. The Yellow Card Scheme could detect this ultra long-latency adverse reaction.

Testing times: the emergence of the practolol disaster and its challenge to British drug regulation in the modern period.

This article analyses how practolol, the first British drug disaster of the modern, post-thalidomide regulatory period, related to the pharmaceutical industry, the medical profession and government regulation of patients' health. Drawing on comparison with the USA, it argues that, contrary to public expectation and perception, the aftermath of thalidomide did not give rise to strident British drug control, imposing the highest possible safety standards on the pharmaceutical industry. Rather, there existed a culture of reluctant regulation that was characterised by continued optimism about, and trust in the purported benefits of new drugs among manufacturers and regulators in the United Kingdom, together with commitment to the protection of the industry and its institutional support for the medical profession. In particular, British regulators were willing to allow new drugs on to the market, fully aware of uncertainty about their safety, but unwilling to be pro-active in issuing warning letters about risks and requiring 'certainty' before acting to withdraw a product. Even after the practolol disaster, the British system was unable to reform itself to construct more rigorous and pro-active monitoring of drug risks. This was because of conflicts with industry interests.

A ranked presentation of the MHRA/CSM (Medicines & Health Care Regulatory Agency/Committee on Safety of Medicines) Drug Analysis Print (DAP) data on practolol.

PURPOSE: To display a ranked presentation of the data given in the Drug Analysis Prints (DAPs) provided by the MHRA/CSM so that the monitoring clinician may be readily alerted to the most important findings. The practolol DAP is taken as an example of the presentation. METHOD: The data for the ranked system organ classes, the ranked deaths and the ranked reaction reports within each system organ class are considered separately. RESULTS: It has been found that there are advantages in considering the system-organ classes, the deaths and the reports of the individual reactions separately and then, within these groupings, providing the mathematically ranked data. The results for practolol, withdrawn due to the associated oculomucocutaneous syndrome, are given as a single worked example. CONCLUSIONS: Presentations of the ranked data arising from spontaneous adverse drug reactions reporting may have useful advantages.

Data-mining analyses of pharmacovigilance signals in relation to relevant comparison drugs.

OBJECTIVE: The aim of this paper is to demonstrate the usefulness of the Bayesian Confidence Propagation Neural Network (BCPNN) in the detection of drug-specific and drug-group effects in the database of adverse drug reactions of the World Health Organization Programme for International Drug Monitoring. METHODS: Examples of drug-adverse reaction combinations highlighted by the BCPNN as quantitative associations were selected. The anatomical therapeutic chemical (ATC) group to which the drug belonged was then identified, and the information component (IC) was calculated for this ATC group and the adverse drug reaction (ADR). The IC of the ATC group with the ADR was then compared with the IC of the drug-ADR by plotting the change in IC and its 95% confidence limit over time for both. RESULTS: The chosen examples show that the BCPNN data-mining approach can identify drug-specific as well as group effects. In the known examples that served as test cases, beta-blocking agents other than practolol are not associated with sclerosing peritonitis, but all angiotensin-converting enzyme inhibitors are associated with coughing, as are antihistamines with heart-rhythm disorders and antipsychotics with myocarditis. The recently identified association between antipsychotics and myocarditis remains even after consideration of concomitant medication. CONCLUSION: The BCPNN can be used to improve the ability of a signal detection system to highlight group and drug-specific effects.

Penetrating keratoplasty for bilateral acute corneal calcification.

A 76-year-old man with bilateral practolol-induced dry eyes developed atypical acute bilateral corneal calcification. Serum calcium, phosphate, and urea levels were within normal limits. The calcium deposition progressed rapidly to involve 90% of the right cornea. Right penetrating keratoplasty was performed with subsequent visual rehabilitation of the patient. Left tectonic penetrating keratoplasty was performed 8 weeks later after corneal perforation. The corneal specimens were examined by light and electron microscopy, which showed an atypical calcareous degeneration involving Bowman's layer as well as the full thickness of the stroma. Transmission electron microscopy showed the granular calcification to consist of extracellular, radially orientated aggregates of fine, needle-shaped crystals. Both transplants remained clear with no evidence of postoperative recurrence. To our knowledge this is the first report of bilateral penetrating keratoplasty for acute calcareous degeneration.

Manifestaçöes reumáticas induzidas por drogas: experiência pessoal e literatura; 1ª parte / Drug induced rheumatic disorders: personal experience and literature; Part 1

Os autores fazem uma revisäo da literatura quanto as manifestaçöes reumáticas induzidas por drogas. Salientam e questionam alguns dos mecanismos envolvidos nas reaçöes adversas as drogas e sua manifestaçöes clínico-laboratoriais, dando enfase ao lúpus-símile. Além disso, alertam sobre a importância em se detectar iatrogenia no curso de uma terapêutica medicamentosa

Safety in clinical trials.

Safety deals with the surveillance and detection of possible threats that can arise against a patient. It might not be an obvious one, like an anaphylactic shock, but a bizarre syndrome of late onset preceded by vague signs or symptoms. To be able to conclude about a possible causal relationship between a drug and such a state with as short a delay in time as possible, the collection and analysis of adverse events during the total clinical trial program of a drug is mandatory. To ask investigators for adverse drug reactions instead is to produce an effective filter, which may help in keeping the incidence figures down in the international data sheet but which also may prove to be hazardous for the pharmaceutical industry in the long run.

Drug-induced immune-complex disease.

A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of C1, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune-complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.

Surgical treatment of constrictive pericarditis due to practolol. A case report.

We report a case of constrictive pericarditis presenting as a late complication of Practolol therapy associated with polyserositis. The patient had a successful result following pericardectomy. This is the first documented case of surgical treatment for Practolol induced constrictive pericarditis.

Conclusiveness of rechallenge in the interpretation of adverse drug reactions.

We here consider the extent to which the presumed correlation between an adverse event and the administration of a particular drug can be reinforced by rechallenge. At first question of terminology is: what is a rechallenge? Rechallenge is often accepted too readily as proof of a causal relationship and clinical examples give illustrations of common misinterpretations. Definitions are proposed to characterize: the outcome of rechallenge; the conditions under which rechallenge is performed. In discussing causality, a sharp distinction is drawn between the outcome per se and the establishment of a causal relationship. Finally, the simple concepts proposed here should permit to establish a typology of rechallenge and to assess, by further experimental or retrospective research, the conclusiveness of rechallenge in interpreting adverse drug reactions.

Drugs in exacerbation of psoriasis.

Drugs that have been associated with the precipitation or exacerbation of psoriasis include lithium, beta adrenergic receptor blocking agents, and antimalarials. The withdrawal of corticosteroids has been reported to activate pustular psoriasis. Nonsteroidal anti-inflammatory drugs, such as indomethacin, have recently been reported to exacerbate psoriasis, although additional well-controlled studies are still needed. Drugs used for treatment of psoriasis will sometimes cause a flare because of irritation, phototoxicity, or hypersensitivity reaction resulting in a Koebner phenomenon. Because psoriasis is a very complex disease and its activity is often unpredictable, clinical studies on adverse drug effects on psoriasis have been difficult to conduct. This review evaluates clinical, histologic, and biochemical evidence in the literature for drug-associated onset or exacerbation of psoriasis.

Drugs affecting the eye.

PIP: This discussion reviews drugs that affect the eye, including antihyperglycemic agents; corticosteroids; antirheumatic drugs (quinolines, indomethacin, and allopurinol); psychiatric drugs (phenothiazine, thioridazine, and chlorpromazine); drugs used in cardiology (practolol, amiodarone, and digitalis gylcosides); drugs implicated in optic neuritis and atrophy, drugs with an anticholinergic action; oral contraceptives (OCs); and topical drugs and systemic effects. Refractive changes, either myopic or hypermetropic, can occur as a result of hyperglycemia, and variation in vision is sometimes a presenting symptom in diabetes mellitus. If it causes a change in the refraction, treatment of hyperglycemia almost always produces a temporary hypermetropia. A return to the original refractive state often takes weeks, sometimes months. There is some evidence that patients adequately treated with insulin improve more rapidly than those taking oral medication. Such patients always should be referred for opthalmological evaluation as other factors might be responsible, but it might not be possible to order the appropriate spectacle correction for some time. The most important ocular side effect of the systemic adiministration of corticosteroids is the formation of a posterior subcapsular cataract. Glaucoma also can result from corticosteroids, most often when they are applied topically. Corticosteroids have been implicated in the production of benign intracranial hypertension, which is paradoxical because they also are used in its treatment. The most important side effect of drugs such as chloroquine and hydroxychloroquine is an almost always irreversible maculopathy with resultant loss of central vision. Corneal and retinal changes similar to those caused by the quinolines have been reported with indomethacin, but there is some question about a cause and effect relationship. The National Registry of Drug Induced Ocular Side Effects in the US published 30 case histories of cataract suspected to be induced by allopurinol; numerous additional cases have been reported to the registry since. Phenothiazine, with an estimated 3% incidence of side effects, appears to be safer than other antipsychotic drugs, but the rate of ocular effects increases with the duration of therapy. Thioridazine and chlorpromazine are known to cause lens deposits and pigmentary retinopathy. There is a significantly high prevalence of thrombophlebitis and pseudotumor cerebri among women who use OCs and thrombotic retinal vascular disease, such as retinal vein occulsion, might be linked with them. It also is probable that, because of altered hydration of the cornea, there is a decreased tolerance to contact lenses.^ieng