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OBJECTIVE: To describe factors associated with vitamin supplement use in a large cohort of adult women. METHODS: California teachers and administrators (n = 133,479) completed a questionnaire on lifestyle factors and medical history. Specific supplement users regularly used at least one specific vitamin supplement in the past year; multivitamin users regularly used a multivitamin; and multivitamin and specific supplement users took a multivitamin and one or more specific supplements. Associations between supplement use and other variables were quantified using means, cross-tabulations, and age-adjusted prevalence odds ratios. RESULTS: Multivitamin and specific supplement users tended to be older and Caucasian. Compared to non-users, they were also leaner (odds ratio [OR] for BMI ≥ 30 kg/m2= 0.6 for specific supplement users with or without multivitamins, and OR = 0.7 for multivitamin only users), and were less likely to be current smokers (OR for current smoking = 0.8 for multivitamin plus specific supplement users, OR = 0.9 for secific supplement only users, and OR = 0.7 for multivitamin only users). Specific supplement users (with or without multivitamins) were more likely to use cancer screening tests, eat fruits and vegetables, and exercise than were multivitamin only users or non-users. CONCLUSIONS: A variety of demographic, dietary, and health-related factors were associated with different categories of supplement use.

The structure-activity requirements for stimulation of striatal dopaminergic mechanisms were investigated using a series of phenethylamine derivatives, apomorphine and isoapomorphine, and the intracerebral injection technique for direct application into the striatum. Asymmetric body posturing (unilateral injections in saline-and haloperidol-pretreated rats) and hyperactive/stereotyped be-behaviour (bilateral injections in nialamide-pretreated rats) were used as indices of dopaminergic stimulation. Of 24 phenethylamine derivatives studied, 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) possessed maximum activity. Alteration in length of the ethylamine side-chain, substitution of the α-C atom (α-methyldopamine) or hydroxylation of ß-C atom (noradrenaline) markedly reduced or abolished activity. Activity was also decreased by N-methyl substitution but epinine was active. The catechol moiety appeared essential for dopaminergic stimulation since the 3- or 4-hydroxyphenethylamines (tyramine, m-tyramine) were inactive and 2-(3,4-methylenedioxyphenyl)ethylamine was only weakly active. The marked dopamine-like activity of the 2-(3,4-diacetoxyphenyl)ethylamine compounds was attributed to their non-enzymic hydrolysis to dopamine in situ.The stereoselectivity of the dopamine-induced effects was assessed using transand cis-2-(3,4-methylenedioxyphenyl)cyclopropylamine. The transconformer was active and the importance of this conformation was further indicated by the inactivity of isoapomorphine compared with apomorphine. It is suggested that the results provide a rational basis for the design of drugs required to stimulate striatal dopamine receptors and that the intrastriatal injection technique may be useful in the detection of potential antiparkinson agents.

A wide variety of phenylethylamine derivatives were injected bilaterally into the nucleus accumbens of rat following a nialamide pretreatment and hyperactivity was recorded. 2-Phenylethylamine was shown to induced a low intensity hyperactivity but the inrroduction of hydroxyl functions on to the phenyl ring at the 3- and/or 4-positions enhanced activity and m- and p-tyramine and dopamine each caused marked hyperactivity in the 0.4–25 µg dosage range. Methylation of one hydroxyl function reduced activity (3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-phenylethylamine); 2(3,4-methylenedioxyphenyl) ethylamine was inactive. Agents with substitution of the side chain, such as noradrenaline, d-amphetamine and a-methyldopamine, were all shown to induced marked hyperactivity at doses of 1.6–25 µg. Alterations in the chain length markedly reduced activity (4-(3,4-dihydroxyphenyl) butylamine, 3,4-dihydroxybenzylamine). A variety of N-substituted compounds were shown to be potent inducers of hyperactivity from the nucleus accumbens (adrenaline, epinine, N-ethyldopamine, N-isopropyldopamine, isoprenaline) (0.2–25 µg). However, N-methyl-N-isopropyldopamine showed only weak activity and N,N-dimethyldopamine was inactive. All hyperactivity effects were shown to be dose-dependent. The hyperactivities induced by dopamine, noradrenaline and isoprenaline were each inhibited in a dose-dependent manner by subsequent injections of fluphenazine (1.25–25 µg) into the nucleus accumbens, although no reductions were recorded following similar injections of saline, solvent, 2% procaine, 50 µg propranolol or 50 µg piperoxan.

Surfactant protein A (SP-A) regulates surfactant secretion via an SP-A specific type II cell membrane receptor (SPAR). We report here that two anti-SPAR monoclonal antibodies can modulate the secretory inhibition caused by SP-A. A2C and A2R are rat monoclonal antibodies raised independently and recognize a 32-kDa protein on rat alveolar type II cell membranes. Immunocytochemical studies show that these antibodies bind to isolated type II cells. Scatchard analysis confirms that SP-A binds alveolar type II cells through a single affinity receptor and shows that A2C and A2R recognize that same receptor. Both antibodies inhibit the binding of125I-SP-A to isolated type II cells. The functional activity of this 32-kDa protein was studied by examining surfactant secretion in isolated type II cells. Surfactant phospholipid secretion was measured in cells that were exposed to various surfactant phospholipid secretagogues (ATP, dibutyryl cAMP, terbutaline, or ionomycin), ±SP-A (100 ng/ml), ±A2C or A2R. Both antibodies block the negative feedback loop by which SP-A inhibits surfactant secretion. This activity of A2C and A2R is dose-dependent and is independent of the secretagogue used. Thus, the 32-kDa type II cell membrane protein bound by A2C and A2R is the functional receptor on alveolar type II cell membranes and regulates type II cell surfactant secretion.

SummaryThe effects of mianserin, a tetracyclic antidepressant, on sleep stages and on the nocturnal secretion of cortisol, ACTH, growth hormone, prolactin and tryptophan were studied on II normal male volunteers in a double-blind, placebo-controlled study. Mianserin increased Stage 3 time (p <0.001) and Stage 4 time (p <0.01). It reduced the number of REM periods (p <0.001), the REM latency after sleep onset (p <0.01) and both the total and percentage REM time (p <0.05). A reduction in both the total sleep time (p <0.05) and the percentage of total time in bed (p <0.05) were the only significant carry-over effects from the drug treatment period. No significant difference in any biochemical measurement was found between placebo and drug treatment.

Forty psychiatric out-patients with primary anxiety entered a double-blind trial comparing 2 weeks of treatment with mianserin 30–60 mg daily or diazepam 15–30 mg daily, followed by 2 weeks of single-blind placebo administration.Both drugs were effective anti-anxiety agents, but mianserin was significantly superior in efficacy as measured by the Physician's Global Rating of Severity of Illness. No differences between treatments were apparent using the Hamilton Rating Scale for Anxiety.There were no significant differences in terms of side-effects, and both drugs increased anticholinergic effects such as dry mouth, blurred vision and constipation over baseline values. With one exception in the mianserin group, all patients who entered placebo treatment became worse.

Synopsis:Rimiterol1is erythro-(3,4-dihydroxyphenyl)-2-piperidyl-methanol hydrobromide, and is a catecholamine. It is a selective β2-adrenoreceptor agonist, but is not effective as a bronchodilator by the oral route of administration. Rimiterol is available at present as an aerosol, though preliminary studies suggest that it may be of value in the intravenous therapy of severe asthma. Clinical studies in asthmatic patients have shown that inhaled rimiterol rapidly produces effective bronchodilatation. Its duration of action is similar to that of isoprenaline and shorter than those of salbutamol or terbutaline, though it may act faster than either of the latter drugs. At doses which produce equivalent maximum ventilatory responses, rimiterol produces lesser effects on cardiac or skeletal muscle than do isoprenaline or salbutamol. The short half-life of intravenous rimiterol, its relatively low cardiovascular toxicity, and the lack of resistance to aerosol rimiterol in patients given prolonged intravenous infusions of the drug, suggest that it may be useful in severe asthma either given alone by the intravenous route or combined with rimiterol given by intermittent positive pressure ventilation. Pharmacodynamic Studies: Inhaled or intravenous rimiterol produces bronchodilatation in animals and normal subjects, and also reverses bronchoconstriction induced by histamine or acetylcholine. Aerosol doses of rimiterol (500μg), isoprenaline (100μg), salbutamol (100μg), and orciprenaline (750μg) produced significant and equivalent reductions in the fall in ventilatory capacity induced in normal subjects by inhaled acetylcholine. Rimiterol appeared to be longer acting than isoprenaline against histamine-induced bronchospasm in normal subjects. Its β2-selectivity by the intravenous route is similar to that of salbutamol and about twice that of isoprenaline, but the potency of both drugs is about one-fifth of that of isoprenaline. Significant rises in heart rate followed inhaled isoprenaline 500 or 1,000μg and salbutamol 1,000μg, but not after rimiterol 500 or 1,000μg, in normal subjects. Administration by intermittent positive pressure ventilation (IPPV) showed no difference between 0.5 % rimiterol and saline in effects on heart rate, which was significantly increased by 0.5% salbutamol. Tremorogenic effects in normal subjects were similar after increasing intravenous doses of rimiterol, salbutamol or isoprenaline. Pharmacokinetic Studies: The pharmacokinetics of rimiterol are very similar to those of isoprenaline. Rimiterol has a short half-life (< 5 min) when given intravenously, is rapidly metabolised, to its 3-O-methyl derivative. When swallowed (oral or aerosol) 50% is excreted as rimiterol (free or conjugated), but after intravenous administration the majority (45 %) is excreted as 3-O-methylrimiterol (free or conjugated). The lung appears to metabolise rimiterol, following bronchoscopic administration. Therapeutic Trials: Inhaled rimiterol appears to be similar in potency and duration of action (11/2to 3 hours) to inhaled isoprenaline. Dose-dependent bronchodilatation was produced by isoprenaline 80 to 1600μg or rimiterol 200 to 7200μg, but tachycardia was already severe following isoprenaline 800μg whereas rimiterol gave only insignificant effects on the heart at the highest dose levels. Rimiterol 500μg was equipotent by aerosol with salbutamol 200μg in bronchodilator efficacy, but the duration of action of salbutamol was more prolonged. Similarly, when given by IPPV, the peak bronchodilator effects of 0.5 % of 0.1 % rimiterol were equivalent to those of 0.5 % salbutamol but were significantly shorter in duration. Heart rate changes were of shorter duration after rimiterol than after equivalent bronchodilator doses of salbutamol by IPPV, but neither drug produced significant changes in heart rate by aerosol. Rimiterol 500μg and terbutaline 500μg were equivalent in peak bronchodilator effects, and neither affected heart rate. Rimiterol (400μg) was faster in onset but shorter in duration than terbutaline (400μg), though most chronic asthmatic patients preferred terbutaline. As would be expected none could subjectively detect the shorter onset of rimiterol, as such patients would be unable to detect the rapid onset of any aerosol bronchodilator. Intravenous rimiterol produced dose-dependent bronchodilatation and increases in heart rate and pulse pressure in asthmatic patients. Isoprenaline was about 8 and 5 times as potent as rimiterol and salbutamol in bronchodilator action, and approximately 16 and 12 times as potent in increasing heart rate. Prolonged, low-dose infusions of rimiterol produced dose-dependent increases in bronchodilatation (which were maintained by subsequent inhalations of drug), heart rate, pulse pressure and skeletal muscle tremor. Heart rate reached equilibrium earlier during the course of rimiterol infusion (0.05 to 0.2μg/kg/min) than salbutamol (0.025 to 0. μg/kg/min), and also declined more rapidly after they had stopped. Side-effects: There have been no reports of significant subjective side-effects following the acute administration of rimiterol by aerosol. Palpitations and skeletal muscle tremor have been observed after high or cumulative doses of inhaled rimiterol, and occur in a dose-related manner following intravenous administration. Contraindications and Precautions: There are no specific contraindications to rimiterol, but it should be given with care to patients with thyrotoxicosis, cardiovascular disease, diabetes mellitus, renal or hepatic dysfunction, and those who are hypersensitive to sympathomimetic substances. Caution is also advised in tnose receiving other sympathomimetic drugs or monoamine oxidase inhibitors. Dosage: Rimiterol is available in pressurised aerosols, which deliver 0.2mg, in each dose. One to three inhalations should be sufficient to provide relief in most cases. It should not be necessary for the patient to take further treatment for at least 30 minutes, or more than 8 treatments a day. Patients should be warned, with frequent reminders, of the dangers of overuse, and children should only be treated with a sympathomimetic aerosol under the supervision of a responsible adult. Preliminary studies suggest that intravenous infusions of 0.05 to 0.2μg/kg/minute of rimiterol may provide effective bronchodilatation in cases of severe asthma. The drug dose should then be monitored by the changes in heart rate in individual patients.

Maprotiline1, 1-(3-methylaminopropyl) dibenzo(b,e) bicyclo (2.2.2) octadiene, is a tetracyclic drug, distinguished from conventional tricyclic antidepressants only by the rigid flexure of itsmolecular skeleton. In contrast to amitriptyline or imipramine, maprotiline has sedative and tranquillising properties in animals, appears to have negligible effects on the cardiovascular system in man, and does not influence the central metabolism of 5-hydroxytryptamine. It is indicated for use in the treatment of all types of mental depression or depressive mood disorders, but seems to offer no compelling advantages over the tricyclic antidepressants. Maprotiline is slowly and completely absorbed following oral administration in man. Its blood half-life is about two days, and dose-dependent steady-state blood levels are attained after one week of repeated administration. Maprotiline is slowly eliminated, principally as metabolites and mostly as glucuronides, with about two-thirds of the dose appearing in the urine and one-third in the faeces. In limited placebo-controlled trials in mixed groups of patients with various types of depression maprotiline has not been shown to be superior to placebo. Controlled trials under standardised conditions in hospital inpatients, outpatients attending hospital clinics, and in depressed patients in general practice, have generally failed to find a significant difference between the antidepressant effects of maprotiline and those of amitriptyline or imipramine, though some trials have suggested that maprotiline is more rapid in its action. Maprotiline appears to have a broad spectrum of activity in the various types of depression, producing significant improvement in about two-thirds of both agitated and retarded patients, though it may be more effective in cases of neurotic depression than in those of the endogenous type. In a comparative trial as prophylactic treatment for affective disorders, maprotiline was significantly inferior to lithium carbonate over one year. Maprotiline causes side-effects similar to those of the tricyclic antidepressants, principally drowsiness and dry mouth. Skin rashes have been markedly more prominent with maprotiline, but in controlled trials there has generally been little to distinguish the drug from amitriptyline or imipramine in terms of the overall incidence and severity of side-effects. Its potential for accidental or suicidal overdosage seems to be similar to that of the tricyclic antidepressants. Maprotiline is usually given orally, though treatment may be initiated by the intravenous or intramuscular routes in cases of severe depression or when a particularly rapid effect is desired. The initial dose in depression in 25mg 3 times daily, or more usually 75mg at night, with twice that amount in more severe or resistant cases. Patients with depressive mood disorders, as well as the young or elderly, may receive 10mg 3 times daily increasing to 25 or 50mg as necessary. The usual range of daily dosage in depression is 75 to 150mg, and it may be advantageous to give this as a single dose taken at night. Depressive inpatients may need at least 150mg daily, and this dose should probably be given from the first day of treatment.

Benserazide, (±)-DL-seryl-2-(2,3,4-trihydroxybenzyl)hydrazine, and carbidopa, (−)-L-α-hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid, are inhibitors of extracerebral aromatic L-aminoacid decarboxylase (dopa decarboxylase). Combinations of benserazide and levodopa1(1:4) or carbidopa and levodopa2(1:10) are used in the treatment of Parkinson’s disease, both to treat new patients and as replacements for levodopa alone. Like levodopa, they appear to have little influence on the disease process, and their role in the long-term management of Parkinsonism is symptomatic and palliative. In comparison with levodopa alone the advantages of levodopa-benserazide or levodopacarbidopa are several, but there is apparently little or no difference between the two combination drugs. Their major advantage is that they allow a marked reduction in levodopa dosage without compromising the therapeutic effect. Benserazide and carbidopa diminish the optimum dose of levodopa by about 70 to 80%. Therapeutic response is often seen within days with full benefit within weeks with the combination, as compared with the months associated with levodopa alone, such that the optimum result at 12 months with combination treatment is reached only at 24 months with levodopa. The more rapid induction of therapeutic benefit is due to an increase in the bioavailability of levodopa and is associated with a much reduced incidence and severity of gastro-intestinal side-effects, particularly nausea and vomiting, which limit the rate at which levodopa dosage can normally be increased. The reduced incidence of these side-effects probably results from reduced gastric irritation. Other side-effects, such as cardiac dysrhythmias and postural hypotension, may also be reduced in some patients on combination therapy as compared with levodopa alone. Levodopa plus benserazide or carbidopa may be given to patients receiving amantadine, or anticholinergic or antihistaminic drugs. Unlike with levodopa alone, combination therapy can be given, without reduction in therapeutic effect, in conjunction with pyridoxine. It is possible to treat more Parkinsonian patients effectively with the combinations than with levodopa alone, especially those in whom optimum dosage of levodopa cannot be reached because of dose-limiting side-effects. Levodopa-tolerant patients show a response to combination therapy no greater than that seen with levodopa alone. The incidence and severity of mental disturbances are similar with the combination drugs to those with levodopa alone. Abnormal involuntary movements, which are the major dose-limiting central side-effects in most patients on levodopa, appear earlier in the course of combination therapy, often by the first week, and may be more frequent. At 24 months there may be a progressive decrease in overall performance capacity in some patients, similar to that observed in patients treated with levodopa alone for 3 to 4 years, consisting of a decreased threshold for dyskinetic manifestations and an increase in the incidence of diurnal oscillations in performance (the ‘on-off’ effect). In the short-term, decarboxylase inhibitors may reduce the incidence and severity of the ‘on-off’ effect, possibly by smoothing out fluctuations in plasma levels of levodopa.

Sodium valproate1has a broad spectrum of anticonvulsant activity, but is structurally unrelated to conventional antiepileptic drugs. Its proposed mode of action is mediated through effects on the function of brain γ-aminobutyric acid (GABA). However, the elevations in brain and cerebellar GABA, and the concomitant reductions in levels of cyclic guanosine monophosphate, occur in animals at dose levels which are unlikely to be achieved during the treatment of epileptic patients. Pharmacodynamic studieshave shown that sodium valproate does not affect the autonomic nervous system, and it lacks significant cardiovascular, renal or respiratory effects. Its effects on the EEG are uncertain, but it does seem to reduce or abolish spike-and-wave activity consistently in epileptic patients. Sodium valproate may have an intrinsic hypnotic action, for a controlled trial in normal subjects has shown the drug to be significantly more sedative than placebo and additive with phenobarbitone. In clinical practice, however, the drug seems to produce increased awareness and alertness in many epileptic patients, possibly as a result of the reduced dosage of other antiepileptic drugs with sedative side-effects although the same effect is also noticed in patients who are on sodium valproate alone. Sodium valproate had no psychotropic properties during a controlled trial in patients with aggressive behavioural problems. Pharmacokinetic studies:Sodium valproate is rapidly absorbed after oral administration, reaching peak blood levels within 1 to 4 hours. A good correlation has not yet been established between daily dose, plasma levels and therapeutic effects, due, among other reasons, to wide interindividual variations. The serum half-life is about 7 to 9 hours, but may be longer in cases of overdosage and shorter in epileptic patients receiving long-term therapy with some other antiepileptic drugs. Therapeutic blood levels appear to be about 50 to 100µg/ml in most patients, associated with an adult daily dose of 1,200 to 1,500mg. Delayed-release forms of dipropylacetic acid may offer some advantages in terms of smoothing out fluctuations in inter-dose serum levels, but have to be administered with care due to large individual variations in release. Sodium valproate is rapidly distributed, reaching the brain of animals in a few minutes, but it is likely that most of the drug, which is strongly bound (90%) to human plasma proteins, is restricted to the circulation and rapidly exchangeable extracellular water. The white matter is reached at a later period. Placental transfer occurs, and the drug produces dysmorphogenic effects in animals. Elimination is rapid, principally in the urine with minor amounts in the faeces and expired air. Renal excretion of unchanged sodium valproate is very small, and animal and human studies suggest that it is metabolised rapidly to a glucuronide conjugate and to products of omega-side-chain oxidation. Therapeutic trials:There are few controlled trials of sodium valproate in the treatment of epilepsy, and evidence of its efficacy comes mainly from open studies. In general, the drug has been given to patients already receiving but usually refractory to other antiepileptic medication, which in some cases has been subsequently reduced in dosage or withdrawn completely. Sodium valproate raises the plasma levels of other antiepileptic drugs, particularly phenobarbitone and primidone, though long-term studies have suggested that these levels may return to normal if treatment is continued. Nevertheless, sodium valproate is effective alone in many patients, either as the drug first used in treatment or as a gradual replacement for previously ineffective medication. There is little evidence for the development of tolerance to its antiepileptic effects in long-term studies. Controlled trials have shown that sodium valproate is significantly superior to placebo when added to the previous antiepileptic medication of patients with various types of epilepsy. In one trial, the drug was indistinguishable from ethosuximide when either drug was given alone or added to other antiepileptic drugs in children with typical absence seizures. Sodium valproate is more effective in the generalised than in the partial epilepsies, and is particularly effective in patients with 3 cycle per second spike-and-wave discharges in the EEG. It may play a useful role in the management of grand mal, mixed grand mal and petit mal, drug-refractory temporal lobe epilepsy, and myoclonic epilepsy. In new patients with typical absence seizures, sodium valproate may become the drug of first choice. Its relative lack of sedative effects leaves intellectual performance unimpaired, which is important in childhood epilepsy. Infantile spasms and the Lennox-Gastaut syndrome respond somewhat less effectively to sodium valproate than they do to the benzodiazepines, though sodium valproate is more effective in myoclonic epilepsy where it may be combined with nitrazepam but not clonazepam. The drug may have a role in the prophylaxis of febrile convulsions. Side-effects:Sodium valproate is remarkably free of side-effects, in the general context of antiepileptic drugs. Gastrointestinal effects (nausea, vomiting, abdominal cramp, diarrhoea) are the most commonly reported reactions, occurring in about 9 to 16 % of adults and about 22% of children. These effects have usually been transient and have only rarely required withdrawal of drug. CNS effects include transient drowsiness and sedation, which can usually be corrected by a reduction in the dosage of other antiepileptic drugs given to the patient and may not therefore be strictly attributable to sodium valproate. Both increased and decreased appetite, with appropriate changes in weight, may occur, and there may be a temporary loss of hair in some patients. Patients receiving sodium valproate, particularly children already on barbiturates, may show worsened behaviour with aggressiveness and hyperactivity which usually disappears on withdrawal of the barbiturate. However, most patients tend to feel more lively and alert. Sodium valproate inhibits the secondary phase of blood platelet aggregation, and this has been reflected in some isolated cases, mainly in children, of prolonged bleeding times and thrombocytopenia. Precautions:There are no specific contra-indications to sodium valproate, and there have been no reports of significant hepatic, cardiac or renal abnormalities attributable to the drug. It has been shown to be dysmorphogenic in animals (but no more so than phenytoin) and it probably should be used in women of child-bearing age only in severe cases of epilepsy or in those who are resistant to other treatment, though this is a matter for clinical judgement. There are no reports of dysmorphogenic effects in humans. Introduction of sodium valproate to existing medication may require concomitant reduction in the dosage of other drugs, especially phenobarbitone and primidone, due to the possibility of raised plasma levels and enhanced sedative effects. Sodium valproate may potentiate the effects of MAO inhibitors and thymoleptics, the dosages of which should be reduced accordingly. Caution should be exercised when the drug is administered with others that may affect blood coagulation or when surgery is contemplated in epileptic patients. Sodium valproate is partly eliminated in the form of ketone bodies, which may result in false positives when testing the urine of diabetic patients. Dosage:Sodium valproate may be introduced alone or added to existing medication, but dosage is individual. Treatment should begin with 600mg daily in divided doses, increasing by 200mg daily at 3-day intervals until control is achieved. This is generally within the range 1,000 to 1,600mg daily. If adequate control has not been achieved after two weeks, the dose may be further increased by stages to a maximum of 2,600mg daily, though some severe cases may require doses in excess of this recommended maximum. An alternative drug may be gradually substituted, initially at low dosage, though combination therapy should be considered only if individual drugs fail to produce adequate control. The same pattern of introduction of sodium valproate should be followed in patients already receiving other antiepileptic drugs. If increased sedation is observed, dosages of barbiturates or other drugs should be reduced as sodium valproate is increased. The dosage of both should be adjusted during the stabilisation period to give optimum control at the lowest combined dosage level. In some cases it may be possible to withdraw other medication entirely, allowing optimum control with sodium valproate alone. Initial dosage in children over 20kg should be 400mg/day irrespective of weight, in divided doses, with spaced increases until control is achieved. This is usually within the range of 20 to 30mg/kg of body weight per day. Children under 20kg and infants should be given 20mg/kg of body weight per day; in severe cases up to 50mg/kg/day. A dose of 50mg/kg should be exceeded only in patients in whom plasma levels are measured; plasma levels of 200μg/ml should be exceeded only with caution, and with monitoring of haematological function.

Dantrolene sodium or dantrolene1is 1-[5-(nitrophenyl)furfurylidene] amino hydantoin sodium hydrate. It is indicated for use in chronic disorders characterised by skeletal muscle spasticity, such as spinal cord injury, stroke, cerebral palsy and multiple sclerosis. Dantrolene is believed to act directly on the contractile mechanism of skeletal muscle to decrease the force of contraction in the absence of any demonstrated effects on neural pathways, on the neuromuscular junction, or on the excitable properties of the muscle fibre membranes. Controlled trials have demonstrated that dantrolene is superior to placebo in adults or children with spasticity from various causes, as evidenced by clinical assessments of disability and daily activities, and by muscle and reflex responses to mechanical and electrical stimulation. It is somewhat less effective in patients with multiple sclerosis than in those with spasticity from other causes. There has been a general clinical impression in controlled trials that dantrolene caused less sedation than would have been expected from therapeutically comparable doses of diazepam. In 2 controlled trials, there was no significant difference between dantrolene and diazepam in terms of reductions in spasticity, clonus, and hyperreflexia, but side-effects such as drowsiness and inco-ordination occurred significantly more frequently on diazepam. Long-term studies have indicated continuing benefit for patients taking dantrolene, though the incidence of side-effects has often been high and there has been a suggestion of exacerbation of seizures in children with cerebral palsy. Dantrolene may be of value in the medical treatment of spasm of the external urethral sphincter due to neurological and non-neurological disease, and animal studies suggest a potential use in the management of malignant hyperpyrexia. Chemical evidence of liver dysfunction may occur in 0.7 to 1 % of patients on long-term treatment with dantrolene, with symptomatic hepatitis in 0.35 to 0.5 % and fatal hepatitis in 0.1 to 0.2 %. The drug commonly causes transient drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea at the start of therapy. Muscle weakness may be the principal limiting side-effect in ambulant patients, particularly in those with multiple sclerosis, and therapy could be hazardous in patients with pre-existing bulbar or respiratory weakness. The dosage of dantrolene has been fixed in most controlled trials, though long-term studies have indicated the need for individualisation of dosage. The initial dose is usually 25mg once daily, increasing to 25mg two, three or four times daily, and then by increments of 25mg up to as high as 100mg two, three or four times daily. The lowest dose compatible with optimal response is recommended.

Synopsis:Tri-potassium di-citrato bismuthate1is a complex bismuth salt stable in colloidal form advocated for the treatment of peptic ulcer. Preliminary placebo-controlled trials in small numbers of ambulant patients with endoscopically proven peptic ulcer, strongly suggest that the compound accelerates the rate of healing of gastric and duodenal ulcer within 4 weeks of treatment. However, trials involving larger numbers of patients followed-up for longer periods are required before a clear verdict on the efficacy of tripotassium di-citrato bismuthate in gastric and duodenal ulcer can be given. There are no reliable data on the effect of the drug on ulcer recurrence rate. Side-effects are negligible and the drug could become an important therapeutic agent in peptic ulcer therapy if results of further study are conclusive. The drug causes dark discolouration of the stools and this should be borne in mind when considering the possibility of the presence of in testinal bleeding. Animal pharmacology:In rats, tri-potassium di-citrato bismuthate reduced the incidence of ulcers in the Shay rat preparation as well as those induced by aspirin, phenylbutazone or cortisone. Glandular ulcers induced by histamine were largely prevented by tri-potassium di-citrato bismuthate in the guinea-pig, but not in the rat. A dose-related healing effect was evident in rats with stress induced ulcers, the greatest effect resulting from the highest dose of 32mg/kg daily in two divided doses. Human studies:The addition of tri-potassium di-citrato bismuthate to human gastric juice in vitro resulted in the formation of a precipitate provided free acid was present. The mode of action of the bismuth compound is not entirely clear but appears to be associated with the formation of a protective layer at the ulcer site probably as a result of chelation with protein and amino acids produced by necrotic ulcer tissue. It may also act in part by inhibiting the action of pepsin or by producing a mucin-like layer and covering the gastric mucosa. Pharmacokinetic studies are lacking, but in a study in 10 patients during treatment with tri-postassium di-citrato bismuthate, there was no detectable bismuth in blood or urine samples obtained at varying times after a dose (Sobotka, 1970). More extensive pharmacokinetic studies are being undertaken in man. Therapeutic trials:Results of well conducted placebo-controlled trials employing endoscopic assessment are encouraging, but are inconclusive because of the rather small numbers of patients involved and the short follow-up. These studies strongly suggest that 4 weeks treatment with tri-potassium di-citrato bismuthate accelerates the rate of healing of gastric and duodenal ulcer in ambulant patients. Usual therapeutic doses of the bismuth compound alleviate symptoms in most patients within the first few days of treatment, although initially antacid therapy may need to be instituted to control symptoms in some cases (see section 4.3.1). To date there are no reliable data concerning the effect of tri-potassium di-citrato bismuthate in preventing ulcer recurrence and suitable studies are needed. Side-effects have been essentially absent. A dark discolouration of the faeces usually occurs and occasionally, also of the tongue. Stool discolouration should be remembered when considering the possibility of the presence of intestinal bleeding. Dosage:The usual dosage is 5ml diluted with 15ml water 4 times daily, to be taken half an hour before each main meal and 2 hours after the last main meal of the day. In resistant cases, particularly duodenal ulcer, the dose is 10ml diluted with 15ml water 6 times daily, taken half an hour before and 2 hours after the 3 main meals. No fluids or antacids should be taken for at least half an hour before or after each dose.

Hydrocortisone 17-butyrate1is a new non-fluorinated topical corticosteroid for use in psoriasis, eczema and other inflammatory dermatoses. In double-blind paired comparisons with other topical corticosteroids, the efficacy of hydrocortisone 17-butyrate 0.1% has generally been indistinguishable from that of triamcinolone acetonide 0.1%, fluocinolone acetonide 0.025% or betamethasone 17-valerate 0.1% in patients with eczema or psoriasis. When applied to the face of patients with atrophy superimposed on rosacea and perioral dermatitis resulting from prolonged use of fluorinated topical corticosteroids, hydrocortisone 17-butyrate 0.1% did not prevent the beneficial effect of systemic tetracycline nor the disappearance of telangiectasis, and tended to be more effective than hydrocortisone 1%. This result suggests that hydrocortisone 17-butyrate may be suitable for long-term use on facial lesions, although the occurrence of moderate rebound eruption in about 10% of patients indicates the need for caution. The findings suggest that hydrocortisone 17-butyrate may be less liable to cause skin atrophy and adrenal suppression than some other potent topical corticosteroids, but trials to date have been too short to allow definite conclusions regarding possible long-term effects and have not involved infants or children.

Synopsis:Tobramycin is a new aminoglycoside antibiotic with a broad antibacterial spectrum in vitro, and pharmacokinetic properties similar to those for gentamicin. Tobramycin is more active than gentamicin against Pseudomonas aeruginosa and active against many gentamicin resistant strains, but is not active against enterobacteriaceae resistant to gentamicin. Theoretically, tobramycin has an advantage over gentamicin against infections caused by P. aeruginosa, but any advantage in clinical practice has yet to be adequately demonstrated. Clinical experience with tobramycin is considerably less than with gentamicin. Whilst tobramycin appears to offer no clear advantages over gentamicin against sensitive organisms it is indicated in infection caused by strains of P. aeruginosa which are resistant to gentamicin, but sensitive to tobramycin. Like gentamicin, tobramycin acts synergistically with carbenicillin and the cephalosporins. The efficacy of the tobramycin-carbenicillin combination has been shown in endocarditis caused by P. aeruginosa which was unresponsive to gentamicin plus carbenicillin. Ototoxicity and nephrotoxicity similar to that seen with other aminoglycosides have been encountered in therapeutic trials with tobramycin and wider clinical experience is necessary to determine the relative incidence of these side-effects with gentamicin and tobramycin used under similar conditions. Antimicrobial activity: In comparative studies, in vitro, tobramycin is more active than gentamicin against clinical isolates of Pseudomonas aeruginosa.Similarly, the inhibitory index, which is the ratio between the serum concentration attained at usual therapeutic doses and the minimum inhibitory concentration, for Pseudomonas aeruginosais higher for tobramycin than for gentamicin. Against Gram-negative bacteria other than Pseudomonas spp.the spectrum of activity of tobramycin is similar to that of gentamicin. For most species the activity of tobramycin is slightly less than that of gentamicin. Gentamicin is consistently more active than tobramycin against Serratia marcescens. Like other aminoglycoside antibiotics, tobramycin is active in vitroin low concentrations against Staphylococcus aureus.Tobramycin is essentially inactive against Streptococcus pyogenes, Streptococcus faecalisand Streptococcus pneumoniae(pneumococci). Many studies have reported the relative activity of tobramycin and other aminoglycosides and of other antibiotics against various bacteria in vitro, but comparisons between studies cannot always be interpreted literally because the activity of many antibiotics in vitro, including tobramycin, is influenced by the nature of the culture media and the presence of certain salts. The sensitivity of P. aeruginosato tobramycin is influenced by the magnesium, and calcium content of the culture media whilst that of all species is reduced by sodium ions. Wide variations in the concentration of these ions may result in divergent MIC values and an inappropriate choice of antibacterial aeent to treat pseudomonas infection. In terms of the therapeutic ratio (LDS0/ED50) tobramycin is the most active of the aminoglycosides in promoting survival in mice infected experimentally with P. aeruginosa. Tobramycin is more effective than gentamicin in suppressing experimental pseudomonas keratitis in rabbits. An increase in the bactericidal activity of tobramycin against some strains of P. aeruginosais elicited by the addition of therapeutic concentrations of carbenicillin. However, as synergy could not be predicted from the susceptibility to the individual antibiotics, there is a need to perform appropriate laboratory studies for each strain. The activity of tobramycin in vivoagainst experimental infection is enhanced by the addition carbenicillin or cephalothin. Such studies provide the basis of controlled therapeutic trials with such antibiotic combinations, but to date such studies have not been reported. Some cross-resistance exists between tobramycin and gentamicin for P. aeruginosa, but is not complete. Pharmacokinetics: The pharmacokinetic properties of tobramycin in persons with normal renal function closely resemble those of gentamicin. In cross-over studies comparing gentamicin and tobramycin in healthy volunteers or in cancer patients with normal renal and hepatic function, peak serum levels after therapeutic doses given by the same route have been similar. Serum levels after intravenous administration are related to the dose and the rapidity of the injection or infusion. Low concentrations of tobramycin are present in CSF after parenteral administration and intrathecal or intraventricular administration is required to achieve therapeutic concentrations. An apparent volume of distribution equivalent to about 30% of the total body weight has been reported by some investigators whilst others have recorded lower values. The serum half-life of tobramycin in several studies has been about 2 hours. There seems to be some uncertainty regarding the degree to which tobramycin is bound to serum proteins. Whilst in one study a value of up to 70% was obtained with therapeutic concentrations, other workers consider that there is little or no serum binding. The latter view is probably correct. After intravenous or intramuscular injection tobramycin is rapidly excreted as the unchanged drug largely in the urine. It appears that the renal excretion of tobramycin, like that of gentamicin, is almost entirely by glomerular filtration. Renal clearance rates in different studies have varied from 76 to 92% of the total clearance. The urinary recovery has varied between 74 and 93% of a 100mg intravenous or intramuscular dose, most of which is recovered during the first 6 hours. The concentration of tobramycin in the urine is highest during the first 2 to 3 hours after a dose and averages about 150μg/ml after a 100mg dose. In patients with reduced renal function serum levels of tobramycin tend to be generally higher than in subjects with normal renal function given an equal dose. As the rate of elimination of tobramycin is related to creatinine clearance and to serum creatinine, the serum half-life is greatly increased in renal failure. Tobramycin is removed from the body relatively slowly by peritoneal dialysis, but is readily removed from the blood by haemodialysis. The cumulative excretion of tobramycin in the urine is reduced in patients with impaired renal function, but urinary concentrations may still be adequate to effectively treat urinary tract infections caused by susceptible organisms. The apparent volume of distribution in renal failure appears to be similar to that in normal renal function. In the newborn, serum levels of tobramycin after an intramuscular dose of 2mg/kg tobramycin vary according to the birth weight and are higher during the first days of life than a week later. The serum half-life is longer in low birth weight infants than in those of higher birth weight. The low urine recovery and increased serum half-life in low birth weight infants may reflect the greater renal immaturity in these infants. In animal studies, tobramycin appeared to be less ototoxic and less nephrotoxic than an equal dose of gentamicin, but the relevance of these studies to humans is not clear at present. Therapeutic trials: In limited therapeutic trials conducted mainly in North America, Europe and the United Kingdom tobramycin has been successfully used to treat infections in the urinary and respiratory tracts, septicaemia, meningitis and infections of the eye, ear, nose and throat and of skin and soft tissue caused principally by Gram-negative bacteria. Comparative trials to date have involved only small numbers of patients. Although the efficacy of tobramycin and gentamicin against infections caused by P. aeruginosaappears to be similar, further suitably designed trials in adequate numbers of patients are needed to determine the relative efficacy of tobramycin and gentamicin against serious infections caused by this species. Results obtained with tobramycin in urinary tract infections have generally been more impressive than those in infections of the lower respiratory tract or of skin and soft tissue. In children with lower respiratory tract infections associated with cystic fibrosis, best results were obtained with tobramycin 10mg/kg daily plus inhalation of 200mg daily. However, administration of a dose in the vicinity of 10mg/kg daily should not be undertaken unless the serum concentration of the drug can be monitored. Septicaemia caused by E. colior Klebsiella spp.responded better to tobramycin at usual dosages than septicaemia caused by P. aeruginosa. There have been only a few cases of Gram-negative meningitis treated with tobramycin reported in the published literature. Results have been fair or poor when tobramycin has been given parenterally with or without concomitant intrathecal injection. It appears that optimum therapy in meningitis is likely to be associated with parenteral plus intraventricular injection particularly in moribund patients who have failed to respond to previous therapy with parenteral plus intrathecal aminoglycosides. Side-effects:The most frequently reported adverse effects thought to be associated with the use of tobramycin have been a reduction in renal function, hearing disturbances and clinical evidence of ototoxicity and alterations in liver function test values. Dosage:The dosage of tobramycin is determined by the body weight of the patient and this must be obtained for calculation of correct dosage. The usual dose in adults and beyond the neonatal period is 1.0 to 1.5mg/kg 8-hourly (3 to 4.5mg/kg daily) in serious infections and 5 to 6mg/kg daily in life-threatening infections. Larger doses may be needed in some life-threatening infections. In neonates the dosage is 2mg/kg 12-hourly (4mg/kg daily) intramuscularly or as a 2-hour intravenous infusion. In patients with impaired renal function serum levels of tobramycin should be monitored whenever possible. Following a loading dose of lmg/kg, subsequent dosage should be adjusted either by giving reduced doses at 8-hourly intervals or normal doses at increased intervals.

Synopsis:Metoclopramide 1 , 4-amino-5-chlorO’2-methoxy-N-(2-diethyl-aminoethyl) benzamide, is advocated for use in gastro-intestinal diagnostics, and in treating various types of vomiting and a variety of functional and organic gastro-intestinal disorders. Published data have indicated that metoclopramide assists radiological identification of lesions in the small intestine, facilitates duodenal intubation and small intestine biopsy, and eases emergency endoscopy in upper gastro-intestinal haemorrhage. Metoclopramide reduces post-operative vomiting and radiation sickness, and ameliorates some types of drug-induced vomiting. It may provide symptomatic relief in dyspepsia and possibly in vertigo, reflux oesophagitis and hiccups, but further controlled trials are needed to confirm the efficacy of metoclopramide in these proposed areas of use. It promotes gastric emptying prior to anaesthesia. Its effects in healing gastric ulcer and preventing relapse of duodenal ulcer remain unproven. Side-effects are few and transient, though alarming extrapyramidal reactions can occur in a small proportion of patients receiving therapeutic doses but more usually following excessive doses in young subjects. They respond rapidly to withdrawal of the drug. Pharmacodynamic studiesin man and in a variety of experimental animals have established that metoclopramide, after oral or intravenous administration, rapidly affects the motility of the gastro-intestinal tract. Its effects include improved resting tone of the oesophageal sphincter, improved tone and peristalsis of the stomach with accelerated gastric emptying (but with slowing in some cases), enhanced pyloric activity, distension of the duodenal bulb, and increased peristalsis of the duodenum with accelerated transit through the duodenum and jejunum. It has comparatively little overall effect on colonic motor activity in vivo. The actions of metoclopramide on motility are blocked by atropine and can be reproduced in vitroon animal and human smooth muscle. It is unclear whether the drug is effective in all post-vagotomy patients. Metoclopramide has no effect on gastric secretion, and may sensitise gut muscle to the action of endogenous acetylcholine. The accelerated gastric emptying usually produced by metoclopramide is reflected in its effects on the absorption of other drugs. Intramuscular metoclopramide promoted the absorption of salicylate from the depressed levels associated with attacks of migraine to those characteristic of normal subjects. Paracetamol absorption was both accelerated and enhanced in normal subjects. Metoclopramide also accelerated absorption of tetracycline and pivampicillin, ethanol, and levodopa, but did not affect that of isoniazid. The absorption of digoxin from slow-release tablets was depressed by multiple doses of metoclopramide given to patients on maintenance digoxin therapy. Metoclopramide is effective in preventing apomorphine-induced vomiting in man, and appears to be equipotent with prochlorperazine but superior to trimethobenzamide. In animals it is a potent antagonist of vomiting induced by apomorphine, hydergine, reserpine, tetrodotoxin and copper sulphate. Metoclopramide has behavioural properties in animals which suggest that it is a central dopaminergic antagonist, and it may exert its anti-emetic effects by blocking the chemoreceptor trigger zone for vomiting. In cats, spontaneous electrical discharges from this part of the central nervous system were abolished by metoclopramide and stimulated by apomorphine. Other effects of metoclopramide on the central nervous system include typical neuroleptic properties in animals; catalepsy and reversal of the behavioural stereotypies produced by apomorphine or amphetamine. In man, however, metoclopramide is without significant antipsychotic or sedative properties. Metoclopramide lacks significant cardiovascular effects, and large intravenous doses in patients with heart disease had no marked influence on haemodynamic parameters. Intracardiac conduction is unaffected by metoclopramide, though large doses prevent experimentally-induced cardiac arrhythmias in animals and produce a slight and transient decrease in blood pressure. Metoclopramide has a negligible effect on blood pressure responses in animals to acetylcholine, adrenaline, histamine and noradrenaline but it blocks the hypotensive action of dopamine. Pharmacokinetic studiesof metoclopramide in man are limited, but animal experiments suggest that the drug is well absorbed and rapidly excreted, with a short half-life and only partial metabolism by O-demethylation, N-de-ethylation and amide hydrolysis. Maximum plasma levels occur within 30 to 120 minutes of oral dosage, and human studies indicate that levels of 0.2gmg/ml are achieved following intramuscular doses of 40mg. Plasma half-life in animals is 1 to 2 hours, and metoclopramide is distributed principally to the intestinal mucosa, liver, biliary tract, and salivary glands. Within the central nervous system the drug is localised at the area postrema, which contains the chemoreceptor trigger zone for vomiting. Metoclopramide binds only moderately to human plasma protein and 24% of the dose was excreted unchanged in the first 24 hours following an intramuscular dose of 40mg in human volunteers. Therapeutic trialsunder controlled conditions have shown that metoclopramide in intramuscular doses of 10 to 20mg is significantly better than placebo in controlling postoperative vomiting. Metoclopramide was also slightly more effective than prochlorperazine (10mg, im) in one study and significantly superior to perphenazine (5mg, im) in one of two studies but there was no significant difference between metoclopramide (20mg, iv) and trimethobenzamide (300mg, iv). The effects of metoclopramide seem to be independent of either the type of anaesthetic or the premedicant used but for optimum effect may need to be given towards the end of the operation. Controlled trials have demonstrated that 10mg intramuscular metoclopramide is significantly superior to placebo, perphenazine (5mg, im), or prochlorperazine (10mg, im) in preventing vomiting due to pethidine or morphine. The drug was effective in women during labour, in the elderly, and in surgical patients, and it abolished pre-operative vomiting associated with pethidine administration. Clinical experience suggests that daily doses of 30 to 80mg metoclopramide are effective in controlling nausea and vomiting in Parkinsonian patients receiving levodopa, without compromising the therapeutic efficacy of levodopa. However, controlled trials show that the drug has no place in relieving emesis induced by some cytostatic drugs or by iodipamide. Radiation sickness was ameliorated by daily metoclopramide, which was not significantly different in its effect from prochlorperazine. Metoclopramide was indistinguishable from prochlorperazine and significantly superior to placebo in a controlled trial in the relief of vomiting of pregnancy, without apparent deleterious effects on the fetus. Clinical experience confirms these effects, but like all new drugs metoclopramide should probably not be given to women during the first 3 months of pregnancy since its safety in use has not been established, despite the lack of dysmorphogenic effects in animals. Limited controlled trials show that metoclopramide may be useful in providing symptomatic relief, particularly from nausea and vomiting, in patients with a variety of disorders. Further controlled trials in large groups of selected patients are needed to confirm these effects. Results of a controlled study indicate that metoclopramide may be effective in treating nausea and vomiting of vertigo and certain associated disorders, but it appears to have no place in the treatment of seasickness. Migraine may respond to the drug, but in the studies to date patients have continued to take their usual analgesic medication, the absorption of which is promoted by metoclopramide. The lack of sufficient controlled trials, however, leaves the role of metoclopramide in these disorders uncertain. Dyspepsia responds to metoclopramide, which was significantly superior to placebo or the anticholinergic drug pipenzolate in controlled trials. Metoclopramide was more effective in controlling nausea, vomiting, epigastric burning, heartburn, and regurgitation of sour fluid than the flatulent symptoms of belching, bloating, and abdominal distension. Nevertheless, there is still some debate as to whether metoclopramide is effective in preventing gastro-oesophageal reflux. Metoclopramide may be useful in treating hiccup. Limited controlled trials suggest that metoclopramide provides symptomatic relief and may accelerate the healing of gastric ulcer and prevent relapse of duodenal ulcer, but its role remains unproven. Some functional gastro-intestinal disorders appear to respond to metoclopramide. In controlled trials, it was significantly more effective than carbachol or placebo in relieving post-vagotomy gastric stasis, superior to placebo in alleviating gastritis and gastroptosis, and as effective as isopropamide plus haloperidol against irritable colon and spastic constipation. It has been used successfully in the conservative management of complete pyloric obstruction due to duodenal ulcer, in order to avoid emergency surgery but it probably should not be used in pyloric stenosis due to carcinoma or severe fibrosis. The dual action of metoclopramide in preventing emesis and accelerating gastric emptying, has established its use in anaesthetic practice. It is especially useful in emergency anaesthesia, including during labour, when rapid clearance of gastric contents is required. Diagnostic uses:In diagnostic radiology or cineradiology, metoclopramide given before barium meal provides excellent conditions for the diagnosis of lesions in the duodenum, jejunum and ileum, and prevents vomiting of barium in nauseated patients such as those with jaundice. It significantly increases the rate of gastric emptying and reduces the transit time for barium to reach the caecum. Controlled trials have shown that small intestine examinations are complete within 1 hour in over 80% of metoclopramide-treated patients compared with in less than 20% of untreated patients. Both oral and intravenous metoclopramide were superior to placebo in speeding gastric emptying and reducing the number of films needed for complete visualisation of the small intestine, but in one study oral metoclopramide gave an increased number of radiographically poor examinations. Metoclopramide is useful in facilitating duodenal intubation ad permitting rapid and successful biopsy of the small intestine, in the absence of significant side-effects. It speeds the passage of biopsy capsules across the pylorus, and was significantly superior to both placebo and pharyngeal anaesthesia in controlled trials. In patients with functional pyloric stenosis, metoclopramide facilitated endoscopic observation of the duodenal bulb. Emergency endoscopy of upper gastro-intestinal haemorrhage is facilitated by the administration of metoclopramide, which clears the viewing area of blood. However, it is possible that the increased stomach activity may in itself cause further haemorrhage. Side-effectswith metoclopramide are usually mild, transient, and readily reversed by withdrawal of drug. A review of one published trial suggests that they occur in about 11% of patients, but the incidence may be different in clinical practice. They consist principally of drowsiness and lassitude, bowel disturbances, and dizziness and faintness. Metoclopramide may increase lactation by stimulating the release of prolactin. Extrapyramidal effects are alarming but uncommon (in about 1% of patients). They consist of dystonic reactions such as trismus, torticollis, facial spasms, opisthotonos, and oculogyric crises, but Parkinsonian-like symptoms are absent. Metoclopramide-induced dystonia occurs more often in females and in the young patient; when it occurs it is usually following excessive doses, but may also occur at normal therapeutic dosage, and resembles in many respects the dyskinesias induced by the phenothiazines. It responds readily to withdrawal of drug, but severe cases may benefit from intramuscular benztropin or diazepam. Children are particularly susceptible, but restriction of the daily dose to 0.5mg/kg usually prevents overdosage in young patients. Signs of overdosage in children usually include extreme irritability and agitation, with muscle hypertonia. Two adult cases of attempted suicide with 360 and 800mg metoclopramide recovered uneventfully following gastric lavage and observation; somnolence and disorientation were reported, but there were no extrapyramidal signs. Contra-indicationsand precautions:Metoclopramide should neither be given with, or within 2 weeks of treatment with monoamine oxidase inhibitors, tricyclic antidepressants, or sympathomimetic drugs, nor to women in the first 3 months of pregnancy, as the safety of use of such associations has not been established. It may potentiate the central action of some antipyschotic drugs, and its own action on the gastro-intestinal tract may be potentiated by acetylcholine-like drugs and blocked by atropine-like agents. It should not be given with phenothiazines. The ability of metoclopramide to provide symptomatic relief in gastro-intestinal disorders does not replace proper investigation and diagnosis of the patient’s symptoms. Metoclopramide should not be given to patients with epilepsy or extrapyramidal syndromes, though it may be safely used in Parkinsonian patients to control vomiting. The dosage for children should be carefully adjusted from initially low levels. Increasing the adult dosage beyond the recommended level does not normally lead to a corresponding enhancement of therapeutic effects. Dosage:Metoclopramide is given before or just after meals, or 20 minutes before symptoms are likely to occur, in oral, intramuscular, or intravenous doses of 10mg, up to 3 times daily, in adults, and 5 to 10mg 2 to 3 times daily in young adults. Children under 14 should receive 1 to 5mg, 2 to 3 times daily, according to age and body weight. The total daily dose in children and young adults should not exceed 0.5mg/kg. For diagnostic purposes, the adult dose is 20mg orally, 20 minutes before examination, or 10 to 20mg by injection 5 minutes before examination. Children receive, according to age and body weight, 1 to 5mg, 5 to 10 minutes before examination.

Tinidazole1, a synthetic imidazole derivative, has been used in the oral treatment of several protozoal infections — trichomoniasis, giardiasis and amoebiasis. Among the protozoal organisms inhibited by tinidazole are Trichomonas vaginalis, Trichomonas foetus, and Entamoeba histolytica. In vitro, tinidazole has been shown to possess antiprotozoal activity at least comparable to, and in some cases greater than, metronidazole. Tinidazole also has activity against some Gram-negative anaerobic bacilli, including Bacteroides spp. Following oral administration of a 2g dose, like metronidazole serum levels peak in about 2 hours but persist for longer. Any clinical significance of the longer plasma half-life (tinidazole 12.5h; metronidazole 7.3h) has yet to be demonstrated. Tinidazole is approximately 20% bound to plasma proteins. Only unchanged drug has been found in the plasma and urine of tinidazole-treated subjects, although metabolites have been detected in animal studies. A single 2g dose of tinidazole has been shown to be effective therapy in vaginal trichomoniasis and in urogenital trichomoniasis in males. Single-dose therapy in general offers advantages in regard to convenience, and in the treatment of a sexually transmissible disease such as trichomoniasis, single-dose therapy facilitates compliance of patient and sexual partner. In comparative studies, tinidazole, in both single-dose and traditional multiple-dose regimens, has been shown to be equivalent and often superior to other anti-trichomonal agents, including metronidazole. In intestinal amoebiasis, tinidazole has been evaluated after both once-a-day and multiple daily dose regimens, with the former giving slightly better results. When both metronidazole and tinidazole were administered in multiple daily dose regimens, the two agents yielded similar cure rates; in one study fewer tinidazole-treated patients required a second course. Tinidazole has also been successful in some cases of amoebic liver abscess, but an advantage over metronidazole has not been demonstrated. Results in the treatment of giardiasis, especially with the single-dose regimen, are promising, and in one study, tinidazole proved effective in infections resistant to metronidazole. Even in large doses, tinidazole has been well tolerated, although rarely vomiting may occur and the patient may need to be re-treated with a multiple dose regimen.

Synopsis: Carbenoxolone sodium1has been shown to accelerate the rate of healing of both gastric and duodenal ulcers, but its overall value in duodenal ulcer is probably less because of the high rate of natural remission of duodenal ulcers. Further studies are required to decide whether it should be used prophytactically to delay ulcer recurrence. Carbenoxolone may act by affecting both the proliferative activity of gastric epithelium and the differentiation of the epithelial cells to produce mucus (as well as favourably altering the physicochemical properties of mucus and by reducing peptic activity), factors which may be relevant to the prevention of acute gastric ulcers. Some studies suggest that carbenoxolone adds to the effect of hospitalisation and bed rest on ulcer healing. Whether bed rest confers additional benefit to the drug’s ulcer healing effect in outpatients is also uncertain. There is no evidence that accelerated healing by carbenoxolone is associated with improved overall prognosis. Carbenoxolone is of greatest benefit in accelerating the healing of gastric ulcers in patients for whom hospitalisation is not possible or desirable, but it should only be used in the ambulatory patient when careful and regular observation of serum electrolytes (particularly potassium), blood pressure and weight is possible and when it is known that the patient will attend regular follow-up. Patients must be educated in the proper use of the drug. If severe mineralocorticoid-like toxic effects such as sodium and water retention and hypokalaemia appear, as they do in a variable proportion of patients but most frequently in those receiving excessive doses, carbenoxolone should be stopped and the complication treated; they respond to thiazide diuretics and potassium supplements, and probably to amiloride given in conjunction with a low dose of a thiazide diuretic. Treatment with carbenoxolone can continue with concurrent diuretic therapy in patients with less severe side-effects. Optimum therapeutic effect in gastric ulcer with the least side-effects is achieved with a dosage of 100mg carbenoxolone tablets 3 times daily for the first week followed by 50mg 3 times daily thereafter, best taken before meals. A lower dosage is desirable in the elderly and in those with liver, cardiac or renal disease. Barium meal or preferably endoscopic examinations should be performed regularly and therapy continued until the ulcer is healed. Dosage for duodenal ulcer is 50mg 4 times daily, in special positioned-release capsules. These are best taken about 20 minutes before meals.

Miconazole2, a synthetic imidazole derivative, is a new topical antifungal agent for use in the local treatment of vaginal, and skin and nail infections due to yeasts and dermatophytes. It is particularly active against Candidaspp., Trichophytonspp., Epidermophytonspp., Microsporumspp. and Pityrosporon orbiculare (Malassezia furfur), but also possesses some activity against Gram-positive bacteria. In vaginal candidiasis, miconazole vaginal cream has produced higher cure rates than conventional nystatin vaginal tablets or amphotericin B vaginal cream. There have been no published comparisons with nystatin vaginal cream or foaming vaginal tablets — the nystatin dosage form preferred by some clinicians. The vaginal cream has also achieved a cure where previous nystatin or natamycin therapy had failed. Miconazole has proved equally effective in both Candidaand dermatophyte infections of the skin, but as yet there have been no published comparisons with other antifungal agents. However, it has been successfully used in chronic skin infections which had not responded satisfactorily to other agents such as natamycin and pecilocin. Preliminary experience with oral and intravenous miconazole therapy in systemic candidiasis is promising. Miconazole preparations are well accepted and tolerated.

The demonstration that long-term administration of relatively low doses of clonidine 2decreased the responsiveness of blood vessels to vasodilator and vasoconstrictor drugs in animals led to its investigation in the prevention of migraine in man. Results of placebo-controlled and open therapeutic trialshave shown that clonidine in low dosages (75 to 150μg daily) isuseful in preventing migraine headaches in about 30 to 50% of patients. A 50% or greater reduction in headache frequency or headache indices3has been reported in 40% of patients in controlled and open studies. Thus clonidine, like other drugs used in the interval therapy of migraine, can be expected to be effective in only a proportion of patients. Although clonidine has not been compared directly with other drugs used in the prophylactic treatment of migraine, the general clinical impression is that it is less effective then pizotifen or methysergide. Because it is relatively well tolerated at dosages of 75 to 150/ug daily it is worthy of a trial, particularly in patients considered to need prophylactic migraine therapy for the first time, and when migraine occurs in association with hypertension. At the dosages used in migraine prophylaxis, which are almost invariably lower than used in hypertension, clonidine does not cause hypotension and can be used in patients with cardiovascular disease. The principal side-effects are drowsiness and dry mouth which tend to diminish as treatment continues.

At doses similar to those used in the treatment of chronic bronchial asthma, intranasal beclomethasone dipropionate is effective in alleviating nasal symptoms of seasonal allergic and perennial rhinitis in about three-quarters of patients. Eye symptoms are not relieved. The carry-over effect of the evening dose is useful in preventing early morning attacks of sneezing. Intranasal beclomethasone dipropionate is useful in controlling symptoms persisting after polypectomy and may possibly delay or eliminate the need for the surgical removal of nasal polyps, which may shrink after several weeks or months of treatment.

Synopsis: Beclomethasone dipropionate2is a topically active corticosteroid used as an adjuvant in the control of chronic asthma when given by inhalation as an aerosol. It is not intended for treatment of acute attacks. It appears that the main difference between beclomethasone dipropionate and other corticosteroids previously used by inhalation is its high topical activity together with a lower systemic activity due to metabolic inactivation of the swallowed portion of the dose. Clinical experience has shown that at doses of 200 to 600μg daily, beclomethasone dipropionate inhaler is preferable to oral corticosteroids, because of lack of side-effects, when adult patients and children who are inadequately controlled by full doses of sodium cromoglycate and bronchodilators, are first considered to need maintenance corticosteroids. Inhaled beclomethasone dipropionate can allow a worthwhile reduction in maintenance doses of systemic corticosteroids in many patients already receiving these drugs and can replace systemic steroids entirely in some patients, particularly when their initial dose of steroids is less than 10mg daily of prednisone or its equivalent. Substitution should be attempted when the patient’s asthma is well controlled on their usual doses of systemic steroids and full doses of other adjuvant therapy. Withdrawal of systemic corticosteroids should be performed slowly and carefully. Because recovery from impaired adrenocortical function caused by prolonged systemic steroid therapy is usually slow, special care is necessary for 9 to 12 months after transfer to beclomethasone dipropionate aerosol until the hypothalamo-pituitary-adrenal axis has sufficiently recovered to cope with emergencies such as trauma, surgery, severe infections or an acute attack of asthma. It is essential that additional therapy including high doses of systemic corticosteroids be used immediately to control any acute exacerbation of asthma which occurs during maintenance therapy with beclomethasone dipropionate aerosol. Tests of adrenal function suggest that beclomethasone dipropionate at dosages of 400 to 800μg daily has little or no adverse effect. The most common side-effect associated with the continuous use of beclomethasone dipropionate inhaler has been oropharyngeal candidiasis, which appears to be dose-related and more common in women than in men. Systemic steroid withdrawal effects, like being generally unwell, and exacerbation of underlying allergic diseases such as allergic rhinitis, have been reported after substitution of beclomethasone dipropionate inhaler for systemic steroids. However, systemic withdrawal effects seldom occur if systemic steroids are withdrawn slowly. Pharmacological Studies:Preliminary investigations indicated that beclomethasone dipropionate possessed certain pharmacological features suited to topical administration in asthma. An alcoholic solution applied under occlusive dressing is about 500 times more active in producing vasoconstriction of normal skin than dexamethasone or betamethasone. At doses normally used in the treatment of asthma, several weeks of therapy with inhaled beclomethasone dipropionate causes no significant suppression of early morning plasma cortisol, or plasma cortisol response to tetracosactrin stimulation in normal subjects. Beclomethasone dipropionate is well absorbed when given orally, but possesses relatively low systemic activity by this route, apparently because of metabolic inactivation during its passage through the liver. This is supported by the finding that whereas an oral dose of 4 to 8mg of beclomethasone dipropionate is required to cause a marked suppression of plasma cortisol, 1mg intravenously causes complete suppression of plasma cortisol in normal subjects. Thus it appears that the high topical activity of beclomethasone dipropionate, together with a relatively low systemic activity due to metabolic inactivation of the swallowed portion of the dose, are the main reasons why therapeutic doses of inhaled beclomethasone dipropionate control asthma without causing important glucocorticoid effects. Therapeutic Trials:Clinical experience with beclomethasone dipropionate inhaler in steroid-dependent asthmatic patients and in those not receiving systemic corticosteroids, indicates that beclomethasone dipropionate inhaler is preferable to oral corticosteroids when patients who are inadequately controlled by full doses of a bronchodilator and sodium cromoglycate are first considered to require maintenance corticosteroids. Inhaled beclomethasone dipropionate can allow a worthwhile reduction in maintenance doses of systemic corticosteroids in many patients already receiving these drugs and can replace systemic steroids entirely in some patients, without causing a deterioration in their asthma, particularly when their initial dose of steroids is less than 10mg daily of prednisone. Substitution should be attempted when the patient’s asthma is well controlled on usual doses of systemic steroids and full doses of other adjuvant therapy. Exacerbations of asthma should be controlled by immediate therapy with systemic corticosteroids. In double-blind comparisons of oral prednisolone and beclomethasone dipropionate inhaler in steroid-dependent asthmatics, the efficacy of 300μg daily of beclomethasone dipropionate was indistinguishable from that of 7.5mg daily of prednisolone and tended to be more effective than 5mg daily of the oral corticosteroid. It appears that increasing the dose of beclomethasone dipropionate above 400μg daily may benefit some selected patients who fail to respond to usual therapeutic doses. A dose of 800μg daily of beclomethasone dipropionate inhaler may allow a greater reduction in maintenance doses of systemic steroids than 400μg daily in patients whose initial dose of oral corticosteroids exceeds 16mg daily (prednisone). However, as oral candidiasis seems to occur more frequently at the higher dosage, there appears to be little advantage in using maintenance doses of beclomethasone dipropionate inhaler greater than 400μg daily in patients receiving 15mg or less of prednisone. As might be expected, there is a tendency for response to beclomethasone dipropionate to be better in patients who have previously shown a good response to systemic corticosteroids than in patients in whom beclomethasone dipropionate was used to supplement oral corticosteroids in the hope of avoiding an increase in maintenance dosage. These patients were generally on a higher maintenance dose of corticosteroids. Although long-term studies to date suggest that there is no loss of control after substitution of beclomethasone for systemic corticosteroids, short-term courses of systemic steroids are required to control occasional exacerbations of asthma. It appears that sodium cromoglycate can be withdrawn in some patients once they are established on beclomethasone dipropionate inhaler, but others appear to benefit from combined therapy. Therapeutic trials in children, suggest that adequate doses of beclomethasone dipropionate inhaler can replace corticosteroids or corticotrophin in most asthmatic children requiring maintenance therapy with these drugs. Many of the children treated with beclomethasone dipropionate inhaler have not been adequately controlled by sodium cromoglycate plus maintenance corticosteroids, but their asthma status has usually been maintained or sometimes improved when beclomethasone dipropionate aerosol has been substituted for systemic steroids. Substitution of beclomethasone dipropionate aerosol for systemic corticosteroids does not generally appear to result in either suppression or acceleration of growth or in obvious suppression of adrenal function. Studies to date have been unable to explain why some patients fail to respond to beclomethasone dipropionate. In some such cases a short course of oral steroid in relatively high dosage before starting beclomethasone has allowed control to be maintained thereafter with beclomethasone dipropionate inhaler alone. The initial maintenance dose of systemic corticosteroids seems to influence the ease with which these drugs can be withdrawn, particularly when fixed doses of 400 to 600μg daily of beclomethasone dipropionate inhaler have been used. Generally, withdrawal of maintenance corticosteroids in steroid-dependent asthmatics treated with beclomethasone dipropionate inhaler has been easier when the daily dose has been 10mg or less of prednisone or its equivalent. The response to beclomethasone dipropionate may also be influenced by the initial lung function and by the inability to inhale effectively, and to some extent, by age. Overall response in children appears to be at least equal to that in adults. Results of insulin stress tests conducted in one study suggest that at usual therapeutic doses the drug has little effect on the hypothalamo-pituitary-adrenal function. Less definitive measurements such as the tetracosactrin stimulation test and resting early morning plasma cortisol levels have generally failed to detect any obvious suppression of adrenal function at usual therapeutic doses. However, adrenal suppression is apparent at dosages exceeding 1,600μg daily. There has been a clear trend for plasma cortisol levels to return towards normal after substitution of beclomethasone dipropionate for systemic corticosteroids. Side-effects:In clinical experience to date there have been no confirmed reports of systemic side-effects with doses of beclomethasone of up to 600μg daily. The most common side-effect associated with the continuous use of beclomethasone dipropionate inhaler has been oropharyngeal fungal infection with Candida albicans.This effect seems to be dose-related and to be more common in women than in men, but has usually cleared readily with appropriate topical antifungal therapy. Steroid-withdrawal effects such as nausea, vomiting, malaise and muscle and joint pains have been reported in many studies in which systemic corticosteroids have been replaced by beclomethasone dipropionate inhaler. The frequency of such symptoms has tended to be greater in studies in which systemic steroids have been rapidly withdrawn. Exacerbation of underlying allergic diseases, such as allergic rhinitis and atopic eczema, formerly controlled by systemic steroids, has occurred in many studies. Dose:The usual adult maintenance dose is 2 inhalations (100μg) 3 or 4 times daily. In children 1 or 2 inhalations should be given 2, 3 or 4 times daily according to the response. Patients with severe asthma should be given a systemic corticosteroid preparation until the asthma is brought under control, and treatment then continued with beclomethasone dipropionate aerosol.

Synopsis:Hexoprenaline1, N,N-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl] hexamethylenediamine, sulphate is a selective β2-adrenoreceptor agonist which is active in man as a bronchodilator by the oral or intravenous routes and by inhalation. It is indicated for use in the treatment of bronchospasm associated with obstructive airways diseases, including asthma, bronchitis and emphysema.

SummaryA double-blind, randomized trial was carried out in 62 female hospitalized patients with affective psychoses to compare the effectiveness and tolerance of mianserin with that of clomipramine. Patients were treated with median doses of 60 mg mianserin (30 to 80 mg) or 150 mg clomipramine (75 to 200 mg) daily for 3 weeks. There were no significant differences between drug treatments as measured by the Hamilton Rating Scale for Depression, the Clinical Global Impressions and the Syndrome Specific Self-Rating Scales. Both drugs produced significant but indistinguishable improvement in depressive symptomatology. The overall incidence of side-effects was low, but clomipramine produced significantly more anticholinergic effects.

SummaryA double-blind, randomized trial was carried out to compare 60 mg mianserin daily with 150 mg clomipramine daily in the treatment of 145 depressed in-patients and out-patients in 4 centres. The results showed that both drugs were effective antidepressants. No significant differences in efficacy could be demonstrated by means of the Hamilton Rating Scale for Depression, the Beck Self-Rating Inventory or the Clinical Global Impressions for either the in-patients or out-patients. Hypotension, dry mouth and tremor increased significantly more in in-patients with clomipramine than with mianserin. At the end of treatment, weight gain was increased significantly more in out-patients after treatment with mianserin. No differences could be demonstrated between the drugs for other side-effects.

SummaryIn a double-blind trial in depressed out-patients, 80 patients received either 30 to 80 mg mianserin daily or 15 to 40 mg diazepam daily for 4 weeks. Most patients received 50 to 60 mg mianserin, or 25 to 30 mg diazepam, daily after the first week. Mianserin was significantly superior to diazepam in antidepressant efficacy from Day 14 to the end of the trial, as measured by the Hamilton Rating Scale for Depression and the Beck Self-Rating Scale, and at Day 28 as measured by the Clinical Global Impressions Scale. All three measures showed that the mianserin group started the trial with a significantly more severe degree of illness than the diazepam group, but this difference was already reversed by Day 14. Side-effects were more frequent with mianserin treatment.

If flexible working options are 'a good thing', this paper asks why there are still some anxieties about the full integration of women part-timers and non-principals into the profession. Using in-depth exploratory interviews with 25 women GPs, it argues that part of the discomfort with women GPs who work part-time in general practice arises from the fact that they occupy a marginal status between the (public) world of work and the (private) world of the family. Ambiguity is unsettling. A key question is where do their loyalties lie? 'Commitment' is both a practical fact and a symbol of more potent anxieties: it is a mobilizing metaphor. This paper also argues that the flexibility issue cannot be understood in isolation from wider social, economic and political changes taking place, both in the fast-changing role of women (and men) in society, and in and around general practice itself. Women part-timers are actively challenging some of the more negative stereotypes which still surround flexible working options. Being on the margins has advantages: change and creativity tend to occur here more than at the centre.

IT is now generally accepted that the two great albatrosses D. exulans and D. epomophora take about twelve months to rear their young, and if successful breed only in alternate years1–4, but the breeding cycles of the smaller species are not so prolonged and there has been less reason to suppose that annual breeding is not the rule. Recent studies at Bird Island, South Georgia (54° 00′ S., 38° 02′ W.) (ref. 5), however, indicate that although the black-browed albatross D. melanophris breeds annually, the grey-headed albatross D. chrysostoma breeds less frequently.

THE exact neurophysiological role of dopamine is still unclear, but it has been implicated in the functioning of the extra-pyramidal motor system (EPS)1,2. Experiments on animals and humans, however, indicate that the smooth functioning of the EPS depends on a fine balance between several biogenic amines3–5. Nevertheless, deficiencies of brain dopamine resulting from degeneration of the substantia nigra seem to be associated with the extrapyramidal symptoms of Parkinson's disease1–6. In accordance with these observations, attempts have been made to raise brain dopamine levels in patients suffering from Parkinsonism. Dopamine itself cannot be used, for it is incapable of crossing the blood-brain barrier, and therefore dopamine precursors, in particular L-3,4-dihydroxyphenylalanine (L-dopa), have been used7–10. Although such treatment apparently relieves the symptoms of hypokinesia, rigidity and posture, tremor is little affected and the necessity for large daily dosage and the side-effects of nausea and hypotension remain as serious drawbacks to the therapeutic use of L-dopa. Stock11has recently suggested that 2-amino-4-hydroxy-6,7-dimethyltetrahydropteridine may be a potential anti-parkinsonism agent since this tyrosine hydroxylase cofactor may be deficient in patients suffering from Parkinsonism12.