Systemic effects of three beta-blocker eyedrops: comparison in healthy volunteers of beta 1- and beta 2-adrenoreceptor inhibition.

The beta 1- and beta 2-adrenoreceptor blockade by means of the systemic diffusion of three beta-blocker eyedrops--timolol, carteolol, and betaxolol--was evaluated in a randomized, single-blind, three-way crossover study in 18 volunteers. The blockade was evaluated by analyzing the variations of the beta 1- and beta 2-blockade effects of isoproterenol before and after instillation of one drop in each eye. The beta 1-blockade effect was judged on the variation of heart rate, and the beta 2-blockade effect was judged on the change in peripheral blood flow measured by veno-occlusive plethysmography. Comparison of the blockade by these drops showed that carteolol and timolol totally inhibited the beta 1 and beta 2 effects of a dose of isoproterenol able to increase heart rate by 50% (placebo eyedrops were used as a control). Betaxolol differ significantly because it allowed the same effects with the same dose of isoproterenol. Intensity of the blockade was measured by comparison of the effective doses of isoproterenol. Carteolol and timolol were shown to be four times more inhibitory.

Systemic and local tolerability of ophthalmic drug formulations. An update.

All eye drops raise problems of local tolerance, but with variable frequencies. They can induce pain on instillation, allergic reactions, delayed healing, punctate keratitis, disturbances of lacrimal secretion, disturbances of accommodation (especially the parasympathomimetics) and local pigmentation after prolonged use. Corticosteroids are associated with 2 major risks: chronic glaucoma and cataract, initially reversible if treatment is stopped. There is still a major risk of corneal herpes with corticosteroids. It is important to be aware of these local problems as they are responsible for poor patient compliance. The systemic effects essentially concern the agonists and antagonists of the autonomic nervous system. beta-Blocker eye drops can cause bronchospasm, heart failure, syncope and psychiatric disorders, especially at high doses and with nonselective beta-blockers. These consequences are usually related to failure to comply with the prescribing precautions. alpha-Adrenergic agonists, which exert dose-dependent effects, can induce hypertensive crises or angina attacks. Apart from patients at risk (children under the age of 30 months and the elderly), parasympathomimetics cause few systemic adverse effects; anticholinesterases, which have curare-like properties, are contraindicated for 6 weeks before general anesthesia. In the very young and the very old, atropinic eye drops carry a risk of cardiovascular collapse and neuropsychiatric disturbances. Problems may also occur with other classes of drugs such as anti-infectives, antispectics, anti-inflammatories and contact lens products. Nevertheless, it is clear that this form of treatment is generally very well tolerated in relation to the volume of eye drops prescribed by ophthalmologists each day.

Bronchial and cardiovascular effects of ocular topical B-antagonists in asthmatic subjects: comparison of timolol, carteolol, and metipranolol.

B antagonists eye drops are most effective for the treatment of chronic open angle glaucoma. By this way of administration they have a very good systemic bioavailability. Bronchial, and cardiovascular effects of three of these topicals: timolol, carteolol and metipranolol have been evaluated in three parallel groups of asthmatic patients. The three topics induce bronchoconstriction without significant difference between them, and lower heart rate (sometimes very intensely) whatever the B antagonist studied. From these data, it is recommended to practitioners to follow carefully the rules of administration of B blockers, even in eye drops.

Dizziness in the elderly and calcium channel antagonists.

Because of the benefit-risk ratio in their favor, calcium channel antagonists are considered to be a safe form of treatment of hypertension in the elderly. However, the outcome of dizziness in some patients over 65 yr old during the first few days of treatment with these drugs has to be considered. Five cases of "malaise" have been mentioned, which occurred during the first few days of treatment. The imputability of the drug in question has been evaluated. Additional factors have been found, ie orthostatic hypotension whatever its mechanism, and association with diuretics, with or without hyponatremia. The above-mentioned cases led to a study in 10 supine elderly women (mean age 85 +/- 3 yr) with normal blood pressure. In this study, systolic and diastolic blood pressure were monitored after a 20-mg oral dose of nicardipine for 3 h. Even in the supine position, a significant fall in blood pressure was observed as early as the 15th min after administration, which could be significant, occasionally reaching 45% of the initial value. Before administering a calcium channel antagonist to an elderly person, orthostatic hypotension has to be investigated. Association with a diuretic results in high risk due to hypovolemia that can enhance the vasodilatory effect of calcium antagonists.

Comparison of propranolol and sotalol pharmacokinetics in obese subjects.

Six obese subjects (mean +/- s.d. : 145.1 +/- 16.7% of ideal body weight) were randomly assigned to a single i.v. dose either of (+/-)-propranolol base (0.108 mg kg-1 of ideal body weight) or of (+/-)-sotalol base (1.06 mg kg-1 of ideal body weight). Each subject received the other drug 7 days later. Pharmacokinetic parameters were compared with those obtained previously in non-obese control subjects. In obese subjects, the pharmacokinetic data calculated for sotalol were comparable with those measured in controls (total body clearance = 9.4 +/- 2.9 L h-1; volume of distribution during the terminal phase = 79.8 +/- 19.8 L or 0.9 +/- 0.2 L kg-1; terminal half-life = 6.2 +/- 1.6 h). For propranolol, total clearance (44.3 +/- 15.9 L h-1) and volume of distribution (230.5 +/- 48.2 L or 2.7 +/- 0.7 L kg-1) were significantly less than control values. The terminal half-life (3.9 +/- 1.1 h), was not significantly increased. These results could be explained by altered tissue blood flow and a decreased metabolic capacity of the liver in obese subjects.

[Effects of beta blockaders on ventilatory function in chronic bronchitis]. / Action des bêta-bloqueurs sur la fonction ventilatoire dans la bronchite chronique.

This study was carried out to determine whether beta blockers could be prescribed for patients with coronary insufficiency and chronic bronchitis. The effects of intravenous infusions (30 mn) of propranolol (30 micrograms/kg), practolol 90 micrograms/kg), atenolol (90 micrograms/kg) and acebutolol (150 micrograms/kg) on vital capacity and expiratory flow rates were investigated in chronic bronchitics. Propranolol (n = 51) moderately reduced the vital capacity and FEV1, by an average 9% and a maximum of 20%. The three other infused agents given to groups of 10 patients did not change the ventilatory function. When the same patients were investigated by cross over with propranol bronchoconstriction was observed. This effect was seen in all stages of chronic bronchitis but was much less severe than in a group of 50 asthmatic patients (-23%). The respiratory tolerance of the cardioselective beta blockers seems to be better but there is considerable individual variation and the diagnosis between asthma and chronic bronchitis may itself be very difficult.

[Drug interactions and the elderly]. / Interactions médicamenteuses et personnes agées.

Elderly people are particularly at risk for drug interactions, for several reasons. They are the part of the population who consume the most drugs: over 75 years the mean number of drugs on a prescription is 5.6. As they suffer from various associated diseases, they see several medical specialists, each of them adding a new prescription to the others. Self-prescriptions complicate the problem because they are rarely mentioned. Changes in pharmacokinetics in the elderly tend to increase blood concentrations of drugs. Elderly people suffer from altered homeostatic mechanisms to compensate for adverse drug effects. As a whole, such individuals are more exposed to the side effects of drugs. The drugs most often involved in these interactions are diuretics, non-steroidal anti-inflammatory drugs, benzodiazepines, antiarrhythmics, cardiac glycosides, antihypertensive drugs, oral antidiabetics and antalgics. The clinical accidents most often occurring with these drug interactions are: malaise, orthostatic hypotension, loss of conciousness, amnesia, confusion, renal insufficiency, digestive problems. Since elderly people are less likely to recover easily, this problem of drug interaction should be looked for systematically.

[Use of calcium inhibitors excluding cardiac pathology and arterial hypertension]. / Utilisation des inhibiteurs des transferts calciques en dehors de la pathologie cardiaque et de l'hypertension artérielle.

Many studies have been done to try to define new therapeutic uses for calcium antagonists, in diseases in which calcium plays a role. Positive results have been obtained in the prevention of acute attacks of idiopathic Raynaud's disease and migraine, and in effort-induced asthma. Some activity could be demonstrated in selected groups of patients with pulmonary hypertension, manic-depressive illness, untractable epilepsy, various functional gynecological or digestive disorders, and in drug-induced nephrotoxicity. A possible effect on the prevention of resistance to anti-cancer drugs could be of major interest. Their antiplatelet effect, and their possible effect against atherosclerosis, which remains to be confirmed, their lack of side-effects in asthmatics and of interference with glucose regulation increase their usefulness in patients with hypertension or ischemic heart disease, especially when other diseases are present.

[Homonymy of drugs: a cause of prescription and dispensing errors]. / L'homonymie des médicaments: une cause d'erreur de prescription et de dispensation.

There have been recently a prescription error and a dispensing error in our department due to drug names which look or sound alike. Errors of this type have frequently been quoted in the Anglo-Saxon literature. The method of choosing a drug trade name is recalled, and a table of French drug names which can involve errors of prescription and dispensing errors is provided.

Effects of beta-adrenoceptors blocking eye drops in patients with chronic bronchitis.

Beta-blocker eyedrops used on asthmatic patients are known to enhance asthma which is, as chronic bronchitis, an obstructive disease of the lung, and an authentic bronchoconstriction is always possible. A single blind parallel trial in 3 groups of 10 patients with grade II and III chronic bronchitis, was conducted to evaluate the cardiovascular and bronchial tolerance of 3 beta-blocker eyedrops: timolol, betaxolol and carteolol compared to placebo. The following parameters were measured during a 90 minutes period: heart rate, systolic and diastolic blood pressure, forced expiratory volume in one second, vital capacity. It appeared that only heart rate lowers significantly under the influence of the beta-blocker eyedrop, the other parameters did not change and no difference was noticed between the three eyedrops. However, comparison of individual values showed a significant decrease of forced expiratory volume in one second in certain subjects and this, although betaxolol is a beta 1 selective beta-blocker. Caution should be taken each time beta-blocker eyedrops are prescribed for glaucoma to patients with chronic bronchitis.

[Oral contraception and troleandomycin]. / Contraception orale et troléandomycine. Un nouveau cas d'ictère.

PIP: A case of jaundice appearing after 7 days of treatment with troleandomycin 1.5 g/24 hours in a 21-year old woman who had taken an oral contraceptive (OC) for 3 years is described. The young woman had tolerated Ovariostat and later Miniphase, and had never taken troleandomycin. Mild digestive trouble appeared after 48 hours, and on the 7th day the appearance of pruritus and early jaundice caused interruption of the troleandomycin and the OC. Examination disclosed hyperbilirubinemia and increased alkaline phosphatases and transaminases. Pruritus and jaundice regressed about 1 month later but did not disappear completely for 2 months. No evidence of viral hepatitus was found. Although combined pills and troleandomycin are both known to be associated with hepatic effects, jaundice is rare in both cases. From 1977-81 about 60 cases similar to the present one have been published in France. If simultaneous treatment with troleandomycin and combined OCs is the cause of the jaundice, the mechanism may be inhibition of troleandomycin metabolism by the estrogen, inhibition of estrogen metabolism by the troleandomycin, or simply the accumulation of toxicities of 2 hepatotoxic substances. Until careful, large scale studies are undertaken it seems prudent to avoid the prescription of troleandomycin in women who are taking combined oral pills or are pregnant.^ieng

[Evaluation of the gastrotoxicity of anti-inflammatory drugs: contribution of general registries of digestive endoscopy]. / Evaluation de la gastrotoxicité des anti-inflammatoires: apport des registres généraux d'endoscopie digestive.

The evaluation of the rate of gastroduodenal toxicity of anti inflammatory drugs is a difficult problem. We tried to analyse that question by studying the general endoscopic registers of the Gastro-Enterologic department of the hospital. This retrospective study concerns 2,945 endoscopies performed during the year 1988 and 1992 randomly chosen among the last 5 years. 992 results show injuries suggestive of non steroidal anti inflammatory drugs (NSAID) toxicity, however only in 65 cases the potential role of an anti inflammatory drug is mentioned: 36 men and 29 women, mean age: 50.6 +/- 19.6 years. Concerning the drugs, only the pharmacological classes they belong to are mentioned except for Aspirin. Acetyl salicylate acid 7 cases, NSAIDS 36 and Steroids 22. In the drug group 63% of injuries are located to the stomach (ulcers 13%, gastritis 50%), 37% to the duodenum (19% ulcers, 18% duodenitis). Compared to the groups with the same kind of injuries, but without any mention of drugs, there are no statistical difference in the proportion of ulcers. Aging and sex are not influent in our results on the genesis of drug induced ulcers. These results must be discussed because a lot of datas are missing in the registers and so the number of patients taking drugs is probably underestimated. This means that unless a prospective study is held with someone enquiring for all the risk factors, the study of the general endoscopic registers is not a good way to estimate gastrointestinal damages due to drugs.

[A survey of self medication. Comparison of results obtained at two centers]. / Enquête sur l'automédication. Comparaison des résultats obtenus dans deux centres.

Authors report results of an investigation led in 2 separate departments concerning 200 subjects: --blood donors: they are by definition healthy subjects who regularly are in touch with a medical structure; --patients with acute traumatic pathology leading to bone surgery consultation. The aim of this investigation was to analyse the different parameters involved in self-medication and to compare their distribution. Self-medication has an overall incidence of 87.5% in these studied groups and has generally been lasting from 2 to 9 years. The main reason for it is the lack of gravity to go and see a physician; although 52% of the patients tested take the advise of another person. The clinical signs leading to self-medication are looked for; 468 different drugs are listed essentially antalogics and drugs for ear, nose and throat as well as respiratory tract diseases. Self prescribed drugs usually come from the familial stock. Blood donors have some specific characteristics. In this population self-medication is more frequent and has been lasting longer. They more often feel able to take themselves in charge, but in contrast ask for the chemist's or the doctor's advise more frequently.

[Drug induced orthostatic hypotension]. / Hypotensions orthostatiques médicamenteuses.

Therapeutic drugs are the main cause of postural hypotension, notably in elderly people. This syndrome is harmful as it reduces patients' compliance with treatment and is responsible for severe accidents. Drugs which lower cardiac output by acting on heart rate and cardiac muscle contractility, and drugs which decrease blood volume may produce postural hypotension; diuretics are often responsible for hypovolemia and hypokalaemia. The principal mechanisms involved are interferences of drugs with vegetative blood pressure regulation. They include vasomotor centre depressors (morphine-like compounds, antihypertensive agents, neurosedatives, neuroleptics, antiparkinsonians); ganglioplegics; inhibitors of noradrenaline production (methyldopa, disulfiram) or re-uptake (antidepressants); catecholamine depressors (guanethidine); drugs acting on chromaffin granules (monoamine oxidase inhibitors) and those which inhibit post-synaptic receptors (alpha- and beta-blockers). Drugs which act on vascular smooth muscle tone (nitrites, calcium channel antagonists, angiotensin-converting enzyme inhibitors) occasionally cause postural hypotension. To the actions of these drugs must be added endogenous and exogenous factors and notably physiological ageing of the baroceptor reflex; these factors must be taken into account whenever therapeutic drugs are prescribed.

[Hepatomegaly with portal hypertension indicative of systemic mastocytosis]. / Hépatomégalie avec hypertension portale révélatrice d'une mastocytose systémique.

Systemic mastocytosis is an uncommon disorder due to multiorgan infiltration by mast cells. The authors report the case of a man whose mastocytosis was revealed in an unusual way by hepatomegaly and portal hypertension of the sinusoidal type. This case was also characterized by the absence of urticaria pigmentosa, the presence of seborrheic warts in which mast cell infiltration was noted and the absence of digestive symptoms. The peculiarities of this case are compared to the published data.

[Psychotic disorders linked to the inhibition of benzodiazepine catabolism]. / Accidents psychiques liés à l'inhibition du catabolisme des benzodiazépines.

Five clinical cases of interaction between benzodiazepines on one hand and erythromycin, troleandomycin, josamycin and cimetidine on the other hand have been analyzed. These interactions resulted in severe disorders of behaviour, amnesia (including amnesia-automatism syndrome in one case), disturbances of consciousness and withdrawal syndrome. These disorders were consecutive to inhibition of the hepatic cytochrome P-450 system. Practical means of avoiding this risk consists in limiting such drug combinations, reducing benzodiazepine dosage and, if a combined treatment is necessary, using by preference either benzodiazepines degraded by conjugation instead of oxidation, or macrolides, or anti-H2 compounds with reduced inhibitory effect on microsomes.

[Phlebitis of the upper limbs on pacemaker electrodes. 4 cases and review of the literature]. / Phlébite du membre supérieur sur sonde de pace-maker. Quatre observations et revue de la littérature.

We report four cases of deep venous thrombosis of the upper extremity, which occurred in two women and two men (mean age 79 years) in whom a pacemaker electrode had been inserted 4 years on averages previously. In three of these four cases phlebitis developed after immobilization of the limb containing the electrode. Deep venous thrombosis of the upper extremity is rare, but 28% of catheterizations are responsible for phlebitis. One to 3% of patients fitted with a pacemaker have symptomatic phlebitis, but these figures rise to 28-65% when phlebography is systematically performed in subjects wearing a pacemaker. The clinical signs are the same as those of the classical forms, and the diagnosis is made by doppler-ultrasonography and by phlebography which informs on the collateral circulation. Cure is obtained with efficient anticoagulant therapy. These cases prompt us to prescribe a preventive subcutaneous heparin therapy in those pacemaker-fitted subjects whose arm is immobilized. The heparin dosage remains to be determined precisely.

[Evaluation of the systemic effects of timolol maleate in eye drops]. / Evaluation des effets systémiques du maléate de timolol en gouttes oculaires.

The systemic effects of timolol eye drops were investigated in 35 patients divided into three groups: 1. (15 asthmatics); 2. (10 non-asthmatic patients suffering from glaucoma); 3. (10 elderly control subjects). A placebo eye drops was given at time 0, the timolol maleate drops were given at time 30 mn. The control parameters were checked every 15 minutes. They did not show variations under placebo. After administration of timolol, systolic and diastolic blood pressures as well as vital capacity remained unchanged. Heart rate decreased in 91% of subjects by a mean: 18.5% and, extreme 38%: Bradycardia was always sino-atrial and there was a dose effect relationship. Also F.E.V., decreased in 13 of the 15 asthmatics and in 2 patients with chronic bronchitis: in 4 patients the decrease in flow exceeded 20%. The importance of timolol in the treatment of open-angle chronic glaucoma is well-established, but the results reported here and else where emphazing frequent risks should induce prescribers to comply with the rules of good use: analysis of previous history, and compliance with general contra-indications to beta blockers. Routine E.C.G. and strict adjustment of dosage is recommended.

[Comparison of the effects of carteolol and metipranolol eyedrops on the ventilatory and cardiovascular functions in asthmatics]. / Comparaison des effets des collyres au cartéolol et au métipranolol sur les fonctions ventilatoire et cardiovasculaire de l'asthmatique.

Systemic effects of two topical B adrenergic blocking agents, carteolol and metipranolol, recently introduced in the treatment of open angle chronic glaucoma, were investigated in two groups of 10 asthmatic patients, according to a controlled trial device. Saline eye drops as placebo, then, 30 mn later beta blocker eye-drops, were instillated at usual dose. Heart rate, systolic and diastolic blood pressure, vital capacity (VC) and expiratory outflow (FEV1), were checked every 15 mn during 90 mn. They did not vary under placebo. After carteolol and metipranolol, heart rate decreased more than 10% in 7 out of 10 patients in each group (extreme individual changes: -16.7 and -25.0%). Bradycardia was always sino atrial. FEV1 was lowered in 3 patients with carteolol and in 6 with metipranolol (extreme individual values: -32.3 and -31.8%). If time is not taken in consideration, the lowest values were -8.6 +/-4.6% with carteolol and -17.9 +/- 3.3% with metipranolol. CV was reduced only in 1 patient under carteolol and 2 patients under metipranolol. Systemic blood pressure remained unchanged. 7 patients complained of ocular pain when metipranolol was instillated. Comparison of both ocular topics shows that metipranolol lowers heart rate and FEV1 more than carteolol, which has a sympathomimetic intrinsic activity. These two drugs have the same clinical efficiency. Our results point out the risks outcoming from their systemic diffusion, and the absolute necessity to comply with the general rules of good use of beta blockers, even with eye drops, mainly the contra-indications and the strict adjustment of individual doses.

[Controlled multicentric study comparing cefixime and amoxicillin in the treatment of lower respiratory tract infections in adults]. / Etude multicentrique contrôlée comparant le céfixime et l'amoxicilline dans le traitement des infections respiratoires basses de l'adulte.

This multicentre, randomized, double-blind study evaluated the effectiveness and safety of cefixime versus amoxicillin. Patients were admitted if they had lower respiratory tract infection with a bacterial pathogen susceptible to both study drugs. Diagnoses included acute respiratory tract infections with no underlying pulmonary pathology (cefixime 21, amoxicillin 27), acute exacerbation of chronic obstructive lung disease (cefixime 32, amoxicillin 42), superinfection of viral bronchitis or lung cancer, and pleuritis (cefixime 10, amoxicillin 6). Patients were treated for at least 10 days with either cefixime 200 mg b.d. or amoxicillin 1 g b.d. A clinical success rate of 80.7 per cent (50/62) in the cefixime group and 82.2 per cent (60/73) in the amoxicillin group was achieved in infections due to susceptible organisms. In acute infections with no underlying pathology, the clinical success rate was 90.5 per cent with cefixime and 81.5 per cent with amoxicillin. Twenty-three cefixime patients and 20 amoxicillin patients were seen 2 to 6 weeks after treatment: there were 2 and 1 clinical recurrences, respectively. All 3 patients were suffering from chronic obstructive lung disease. The bacteriological eradication rate at the end of treatment in assessable patients was 94.7 per cent (17/18) with cefixime and 80 per cent (16/20) with amoxicillin. Six and 11 new organisms appeared, responsible for 2 superinfections under cefixime and 7 under amoxicillin. Treatment was well tolerated by 96.4 per cent of cefixime patients and 90 per cent of amoxicillin patients. This study confirms the value of cefixime as a new oral antibiotic in the treatment of lower respiratory tract infections in adults.