Medical toxicology and adverse drug experience最新文献

In a 21-year-old subject, methanol intoxication was undiagnosed for 12 hours after admission. Only bicarbonate treatment was given during this period, although treatment later included ethanol and haemodialysis. The maximal blood methanol and formate levels were 143 (44.7) and 54.3 mg/dl (11.8 mmol/L), respectively. The delayed diagnosis uniquely allowed for an estimate of methanol elimination kinetics. Before specific treatment, methanol elimination was of zero-order, with a rate of 8.5 mg/dl/h. After admission, the formate levels remained relatively constant until blood pH was normalised by bicarbonate treatment. From this point the formate levels declined, despite an unchanged methanol elimination, indicating that the formate was eliminated faster than it was formed from methanol. Thus, formate elimination may be pH-dependent and aggressive treatment of the acidosis may increase this elimination.

Vancomycin has been in clinical use as a potent antistaphylococcal antibiotic for over 30 years. Most reports of ototoxicity and nephrotoxicity have been associated with early, relatively impure, formulations of vancomycin. This paper reviews the literature concerning vancomycin ototoxocity and nephrotoxicity and the evidence for their correlation with the therapeutic serum concentration range. There have been 28 reports of vancomycin-associated ototoxicity published in the medical literature since 1958. It remains unclear whether any diminution in hearing is permanent or reversible. Few patients in the literature had follow-up audiometry and the hearing impairment tends to be at higher frequencies. Several authors reported peak serum vancomycin concentrations, but the exact time these were drawn with respect to the last dose is mostly unclear. In other reports, the 'peak' concentrations noted 3 to 6 hours after the last dose are probably indicative of much higher concentrations because of vancomycin's rapid phase of distribution. More than half the 57 cases of reported nephrotoxicity due to vancomycin occurred within the first 6 years of the drug's use. Many of these patients also had pre-existing renal dysfunction or were concomitantly receiving other nephrotoxic agents. It is unclear whether the coadministration of aminoglycosides produces a synergistic toxicity. The exact incidence of nephrotoxicity is uncertain, but is probably less with the current, relatively pure, product. The correlation of nephrotoxicity with certain serum vancomycin concentrations remains to be clarified. Other aspects also require clarification, such as when to draw samples to determine peak serum concentrations and whether or not routine measurements are necessary at all. In the absence of better guidelines, efforts should be made to tailor individual patient's regimens to produce peak and trough serum vancomycin concentrations to within the widely accepted ranges of 30 to 40 and 5 to 10 mg/L, respectively. In addition, the concomitant use of other potentially nephrotoxic and ototoxic agents should be avoided.

In recent years, considerable attention has been focused on the pressor effects of nonprescription sympathomimetic agents. The impact and usage of these agents especially ephedrine, pseudoephedrine, phenylpropanolamine and phenylephrine, in hypertensive patients has been the topic of constant debates. The present review is an attempt to report and evaluate all the clinical trials and cases of pressor reactions associated with these 4 agents. The study protocols used in these clinical trials are examined and comments made on any diversion from the standard design. Many factors are found to cause the discrepancies in the data available. It is concluded that ephedrine and phenylpropanolamine are best avoided by hypertensive patients due to higher probability of causing pressor reactions. Data on pseudoephedrine and phenylephrine appear to indicate non-significant effects on blood pressure of normotensive subjects when used at the recommended oral dose as nasal decongestants. Phenylephrine is also commonly employed in nasal and eye drops and the limited data available appear to support its usage in hypertensive patients. However, it is noted that most of the clinical trials involve normotensive subjects and the majority of the results could not be verified due to inadequacies in the study design. This paucity and inconclusive information on hypertensive patients warrants further investigations with emphasis on the study protocols used.

Many organophosphate compounds are pesticides widely used for the control of insect vectors. They are not ideal agents because they lack target vector selectivity, and have caused severe toxicity and even death in humans and domestic animals. Their toxicity has been recognised since the 1930s, when they were also developed for use as chemical warfare agents. The mechanism of action of organophosphates has been determined in some depth; the understanding of the toxic effects resulting from the inhibition of cholinesterase activity, causing accumulation of acetylcholine at nerve endings has played a major part in providing a rationale for specific antidote treatment using atropine and oximes. However, the most suitable oxime for reactivation of cholinesterases has still not been established with certainty, although pralidoxime is widely recommended. Chronic toxicity, particularly the neuropathic effects, merits further study because it contributes substantially to the long term morbidity in cases of severe acute, or chronic, exposure. Prevention of potentially toxic organophosphate exposure, particularly amongst employees in industries manufacturing or using the compounds and in the most susceptible groups of the population, such as the young and the elderly, should be sought wherever possible. Government authorities should be encouraged to control organophosphate product licensing, manufacture, storage, import, methods of use and delivery, food contamination and disposal.

The efficacy of the benzodiazepine-antagonist flumazenil (Ro 15-1788) was evaluated in 26 patients with coma due to benzodiazepine self poisoning, alone or in combination with alcohol or other psychoactive drugs. 77% of the patients responded to the administration of a mean dose of 1.73 mg (range 0.2 to 8 mg) with immediate awakening or an improvement of at least 2 coma grades. In the patients without response (n = 3) or with minor improvement (n = 3) other psychoactive drugs turned out to be predominantly responsible for their comatose state. Adverse effects of flumazenil treatment such as altered blood pressure or increased heart rate were observed, but were generally mild. An acute benzodiazepine withdrawal syndrome was seen in 2 cases. In conclusion, flumazenil proved to be effective in the treatment of severe benzodiazepine intoxication. Beyond that, in cases of mixed overdosage or initially unknown diagnosis the antidote assisted in the clarification of the clinical condition.

Oral retinoids, synthetic derivatives of vitamin A, have been used in the treatment of various dermatoses over the last decade. The most useful drugs have been isotretinoin (13-cis-retinoic acid) for nodulocystic acne and etretinate for psoriasis vulgaris. Retinoids are also effective in the treatment of papulosquamous dermatoses other than psoriasis (i.e. inherited disorders of keratinisation), cutaneous T-cell lymphoma and in chemotherapy and chemoprevention of cancer. However, systemic administration of these compounds is frequently associated with mucocutaneous side effects, liver toxicity and abnormalities of serum lipid profiles, which might be related to an increased risk of coronary heart disease. Of particular concern is the teratogenic effect of all retinoids, which limits their use in women of child-bearing potential. Chronic toxicities from long term therapy with retinoids may result in skeletal abnormalities, usually mimicking diffuse idiopathic hyperostosis syndrome. Furthermore, the chronic use of retinoids in children may inhibit their growth due to premature epiphyseal closure. In contrast to other side effects of retinoids which are dose dependent and reversible upon withdrawal of the drug, it seems unlikely that bone abnormalities will resolve after discontinuation of the medication. In view of the wide spectrum of toxicities, treatment with retinoids requires appropriate selection of patients, careful consideration of the benefit to risk ratio for each individual, periodic monitoring of clinical response and laboratory tests. Clinicians should use special management techniques in order to prevent or minimize slide effects. Extensive investigations are currently being conducted in an attempt to develop new retinoids which will improve the therapeutic efficacy and reduce unwanted reactions.

This is a report of a consensus conference on the management of the benzodiazepine-dependent patient. While the focus is on patients who are already dependent, it is better to avoid dependence in therapeutic use by careful patient selection, low dose and short term administration. The management of dependence can normally be undertaken in general practice unless there are complicating factors, e.g. concomitant severe medical, psychiatric or social problems. Inpatient management is also preferable for those abusing drugs in the sociorecreational area. Withdrawal should be achieved by gradual dosage reduction over a period of several weeks. Support from the practitioner, family and friends is important to achieve good results. Since postwithdrawal problems occur, good clinician support is necessary over at least the next year. Despite the risk of dependence, it is stressed that benzodiazepines are valuable therapeutic agents for several psychiatric and physical disorders.

Accidental ingestion and overdose of medications used in thyroidal illnesses may occur because of the frequency of these diagnoses. This review discusses acute overdosage of 4 groups of medicines. Acute ingestion of thyroid replacement medications occurs very frequently. Overdosage in children is usually asymptomatic and a benign condition; after evacuation of the stomach, propranolol may be used to treat symptomatic children. Other therapeutic regimens are rarely indicated in this age group. Ingestions of large amounts of antithyroid medications occur very rarely and limited information regarding treatment is available in the medical literature. Acute ingestion of iodine often results in corrosive injury of the gastrointestinal tract and renal damage. Cardiopulmonary collapse secondary to circulatory failure, oedema of the epiglottis and aspiration pneumonias may cause death. Administration of starch and sodium thiosulphate, maintenance of airway and stabilisation of circulation are the major components of therapy. Acute overdosage of beta-blockers is uncommon but can be lethal. Patients may appear well initially but they can suddenly develop convulsions and profound cardiovascular collapse requiring instant aggressive therapy. Potassium and glucose concentrations should be monitored. The usage of atropine, isoprenaline (isoproterenol), glucagon and prenalteral is discussed.

In this article the pharmacological management of accidental drug overdose is discussed, with various treatments for overdose proposed, as supported by clinical facts and speculation. Current knowledge is outlined concerning dacarbazine, nitrosourea compounds, melphalan, procarbazine, cyclophosphamide, VP-16.213, l-asparaginase (colaspase), 6-mercaptopurine, mustine (nitrogen mustard), intravenous or intrathecal methotrexate (amethopterin), cytarabine (cytosine arabinoside), fluorouracil and bleomycin.