Search

A simple paper chromatographic method for separation and quantitative determination of tetracycline in pharmaceutical preparations was developed. The method is based on the complexation of the antibiotic with a mixture of urea and disodium edetate on a chromatographic paper at pH 7.4. Spots of tetracycline and its degradation products were located under UV light, and their respective Rf values were calculated. The method can be used to determine tetracycline phosphate, even in the presence of oleandomycin. The developed method proved satisfactory in monitoring the stability of the antibiotic base and its hydrochloride.

A paper chromatographic method for the quantitative separation and determination of oxytetracycline in the presence of its degradation products is presented. The separation of the antibiotic was carried out by making use of its complexation with urea on the chromatographic paper. Oxytetracycline and its degradation products gave characteristic fluorescence under UV light, and their respective Rf values were given. The recovery of this method was satisfactory (mean deviation = −3.0%) and was sucessfully applied to the assay of oxytetracycline in bulk and other pharmaceutical dosage forms. Hydrocortisone acetate and polymyxin B sulfate did not interfere with the chromatographic separation.

METHAPYRILENE hydrochloride is marketed both as an antihistaminic and as a soporific drug under various trade names.1 As a soporific it can be purchased in any quantity without a prescription. Reports of its toxicity have been based chiefly on animal experiments.2,3 Wyngaarden and Seevers4 reviewed the literature on the toxicity of antihistaminic drugs in human beings. They recorded 11 fatal cases, 8 being in children under two years of age. Of the 3 deaths in adults, 1 was a suicide with Benadryl.5 Only 1 of the 11 cases was poisoning with methapyrilene hydrochloride.6 No toxicologic data on blood or . . .

A review of literature on the ocular toxicity of the anti-tuberculosis drug Ethambutol Hydrochloride. Ethambutol Hydrochloride is currently extensively used in tuberculosis therapy, so this review should be of interest to those who are concerned with patients under chemotherapy for tuberculosis.

The commonest current methods employed for testing the action of neoarsphenamine are those in which the drug is injected into mice or rats already lightly or heavily infected with Trypanosoma equiperdum on a previous day. Blood specimens removed from every animal are examined daily, involving the counting of many squares of the counting-chamber, before deciding whether or not the animals are cured. These methods are laborious and time-consuming, and for this reason, and because of other disadvantages, Bülbring and Burn1 proposed that the activity of a preparation should be estimated from the survival times of mice infected and treated on the same day. In the present work, this method has been extended and examined statistically.

n/a

n/a

In previous reports [153, 155, 156, 158] we described the properties of a group of chemically nonrelated substances, such as Phenylbutazone, Chloropromazine, local anesthetics, etc. to prevent blood cell aggregation of the type that may lead to thrombosis, namely red cell and platelet aggregation. These properties were present both in vivo and in vitro and seemed to be mediated by some type of membrane action [158]. They were termed “Anti-Adhesive Drugs”.

Recent reports of considerable variation in the serum levels, and therefore in the probable biological activities, of equal doses of certain drugs marketed by different manufacturers, focus attention upon an important determinant of drug efficacy. These variations indicate that therapeutic equivalence, or equal biological activity, cannot necessarily be inferred from equivalence in the chemical constitution of different formulations of the same drug. In the Drug Efficacy Study, it has been found that, in many cases, no data bearing on biological activity of chemically equivalent drugs are available other than those submitted by the manufacturer who originally filed a New Drug Application for his product. For this reason, the following qualifying addendum was approved by the Policy Advisory Committee of the Drug Efficacy Study and was forwarded to the Food and Drug Administration with each of the 26 groups: Drugs of identical chemical composition (so-called generic drugs) formulated and marketed by

A patient who developed thrombocytopenia while taking analgesics was found to have circulating antibody to a metabolic product of N-acetyl-p-aminophenol (NAPA), but not to the drug itself. The antibody reacted in vitro with an antigen present in the blood of a normal volunteer who had ingested NAPA. The antigenic material was purified from the urine of this volunteer and shown to be the sulfate conjugate of the drug. These findings demonstrate that a drug metabolite may be antigenically active in drug-induced thrombocytopenia when the drug itself is immunologically inert, representing a form of drug-induced thrombocytopenia.

1 Methods for the investigation of possible interactions with tricyclic antidepressant drugs are described. These methods have been applied to a new compound, Ciba 34276-Ba, which has been shown to have antidepressant activity. 2 In five normal volunteers tested before and during treatment with Ciba 34276-Ba, no abnormalities of resting or post-exercise electrocardiographs occurred. A three-fold reduction in tyramine-responsiveness was seen in three normal subjects studied, but no potentiation of the noradrenaline pressor effect occurred. One of six patients given Ciba 34276-Ba whilst on long-term treatment with bethanidine showed loss of blood pressure control. 3 The metabolic clearance of antipyrine was unaltered in two subjects studied, showing no evidence of induction or inhibition of hepatic microsomal oxidizing enzymes by Ciba 34276-Ba.

Following the administration of diazepam to mothers in labour the clinical effects, changes in thermogenesis, and metabolism of the drug in the newborn were observed under carefully controlled conditions. A total maternal dose of 30 mg or less in the 15 hours before delivery had little effect on the infants' state. Larger doses, however, were accompanied by low Apgar scores at birth, apnoeic spells, hypotonia, reluctance to feed, and an impaired metabolic response to a cold stress. Measurement of plasma levels of diazepam and its active metabolite showed that both products were detectable in significant concentrations in some infants for up to eight days. We conclude that greater care should be taken in the use of this otherwise effective drug for the treatment of pre-eclampsia.

1 A specific gas-chromatographic method was developed for determination of N-acetylprocaine amide in plasma and urine, using 4-amino-N-(2-piperidinoethyl)benzamide as an internal standard. The investigation was performed in 50 cardiac patients who had reached steady-state plasma concentrations of procaine amide. 2 The plasma concentrations of the acetylated metabolite varied between 1.0 and 15.0 μg/ml and were thus of the same order of magnitude as those of the parent drug. Especially high plasma levels of the metabolite were seen in patients with poor kidney function. 3 The urinary excretion of the metabolite varied markedly between individuals and ranged between 6 and 52% of the administered daily dose. There was a clear tendency towards higher rates of acetylation of procaine amide in patients with short plasma half-lives of isoniazid, i.e. the phenotype rapid acetylators. Because of coexisting therapy with other drugs and impaired renal function in some patients studies are required in healthy human volunteers to ascertain whether the acetylation of procaine amide and isoniazid are mediated by the same enzyme system.

1 The plasma elimination half-life of mexiletine was measured in four subjects when the urine was rendered (a) acidic and (b) alkaline. 2 Urinary acidification (pH 5.0) was associated with a plasma elimination half-life of 2.8 h and 57.5% of the intravenous dose was excreted in the urine within 48 hours. When the urine was alkaline (pH 8.0) the half-life increased to 8.6 h with negligible amounts of drug appearing in the urine. 3 Urinary pH varies widely in cardiac patients and should be controlled or monitored to provide better therapeutic precision with mexiletine.

Different groups of patients in a general practice have been under close observation by defined methods to assess the extent of their adherence to drug schedules. Patients taking antibiotics, admitted to a short drug trial and prescribed long-term treatments, proved in most cases to be compliant. Antenatal patients taking a once-daily dosage of prophylactic iron were more co-operative than those taking divided dosages. Socially isolated patients and those of low social class were particularly likely to neglect their drugs. It is suggested that the significance and extent of the problem have been largely ignored and that all drug trials undertaken on outpatients should incorporate methods of detecting defaulters.

A 14-day, single-blind trial of prednisone, aspirin, and placebo was carried out in 128 patients suffering from rheumatoid arthritis, using subjective criteria only (severity of pain daily on a pain chart and assessment of the drug for effectiveness). The average treated pain rating, mean patient satisfaction rating, and mean number of days withdrawn from each drug all showed significant differences between prednisone, aspirin, and placebo. Of various pretreatment observations, only the initial pain score and articular index of joint tenderness were significantly related to the average treated pain rating. The trial method is simple and allows many patients to participate without being time consuming for patient or physician. The method seems to have potential in comparing the comparative effectiveness of anti-inflammatory analgesics used in the treatment of patients with rheumatoid arthritis.

Oxprenolol, a new beta-receptor blocking drug with intrinsic sympathomimetic activity, was used to treat 63 episodes of cardiac arrhythmia occurring in 43 patients with acute myocardial infarction or myocardial ischaemia. The drug was most effective in abolishing ventricular ectopic beats and supraventricular tachycardia. The best method of administration was by continuous intravenous infusion and the most satisfactory bolus does was 6 mg. The main side effect was hypotension, which occurred in 59% of episodes of arrhythmia that had responded previously to intravenous administration. Oxprenolol was often effective in lignocaine-resistant arrhythmia. The two main advantages of oxprenolol over propranolol are the reduced likelihood of adversely affecting myocardial function and the diminished tendency to produce bronchospasm.

1. The metabolic fate of [3H]terbutaline has been studied in dog after oral, intravenous and subcutaneous administration and in rat after oral and intravenous administration. In 3–4 days the dog excreted 75% of the dose in the urine after oral administration and more than 90% after intravenous or subcutaneous administration; the remainder was in the faeces. The rat in 24 h excreted about 13% in the urine and 61% in the faeces after oral administration and 48% in the urine and 35% in the faeces after intravenous administration.2. After oral administration of [3H]terbutaline, the time course of radioactivity concentration was the same in lung, heart and serum; low levels of unchanged drug were found in all tissues. After intravenous administration, the concentration of unchanged drug was higher in lung and heart than in serum.3. In dog, 1·7% of an intravenous dose was excreted into bile in 6 h. In rat, about 37% of the dose was recovered in the bile during 12 h.4. Enzymic hydrolysis of urine showed ...

Patients in general practice complaining of insomnia of recent origin have been studied in order to ascertain which factors may be of value in the detection of those more susceptible to drug dependence. The type of sleep disturbance was found to be of importance and a personal disturbance scale was found useful as a screening test in two-thirds of the patients. No difference was found in the development of dependence on amylobarbitone and nitrazepam. One of the most important factors in the prevention of drug dependence seems to be frequent review by the doctor after the first prescription and his cautionary advice to the patient.

Forty patients with various disseminated malignant tumours were treated with up to six antitumour drugs given for periods not exceeding 24 hours. Complete or partial objective tumour regression was achieved in 20 patients. No regression occurred in the remaining 20. Treatment given in this way seemed to be at least as effective as other multiple drug regimens and had the following advantages: (1) toxicity was reduced to a minimum and no access was needed to sterile rooms or platelet transfusions since severe bone marrow depression did not occur, and (2) the patients spent only a very short time in hospital.

A follow-up study of girls in a London remand home during the years 1966-8 showed that 20.6% of those taking non-narcotic drugs on admission, but only 1% of non-drug-taking control admissions, had used narcotics by June 1970. Narcotic use on admission and progression to narcotic use were associated with frequent drug taking, marked involvement in a drug milieu, and a high incidence of personal morbidity. Adolescents who use illicit drugs and have a history of court appearances for any reason are particularly vulnerable to subsequent narcotic usage and other forms of serious drug abuse.

1. The fate of sulphadimethoxine (2,4-dimethoxy-6-sulphanilamidopyrimidine) was studied in man, rhesus monkey, dog, rat, guinea pig and rabbit. 2. About 20-46% of the dose (0.1g./kg.) of the drug is excreted in the urine in 24hr. in these species, except the rat, in which only 13% is excreted. 3. In man and the monkey sulphadimethoxine N(1)-glucuronide is the major metabolite in the urine. In the rabbit and guinea pig N(4)-acetylsulphadimethoxine is the main metabolite. In the dog the drug is excreted mainly unchanged. In the rat equal amounts of the unchanged drug and its N(4)-acetyl derivative are the main products. 4. Small amounts of sulphadimethoxine N(4)-glucuronide are found in the urine of all the species. Sulphadimethoxine N(1)-glucuronide occurs in small amounts in the urine of rat, dog and guinea pig; none is found in rabbit urine. 5. Sulphadimethoxine N(4)-sulphate was synthesized and found to occur in small amounts in rat urine. 6. Monkey liver homogenates fortified with UDP-glucuronic acid are able to synthesize sulphadimethoxine N(1)-glucuronide with the drug as substrate. Rat liver has also this ability to a slight extent, but rabbit liver is unable to do so. 7. Sulphadimethoxine N(4)-glucuronide is formed spontaneously when the drug is added to human urine. 8. The biliary excretion of the drug and its metabolites was examined in rats. The drug is excreted in rat bile mainly as the N(1)-glucuronide. The N(1)- and N(4)-glucuronides administered as such are extensively excreted in the bile by rats.

Measures of subjective feeling used by five patients indicated that depression of mood occurred about four days after fenfluramine withdrawal. An experiment in which another 11 patients took fenfluramine 80 mg for 28 days confirmed the depression, maximal on the fourth withdrawal day. It also indicated that in the first week of administration there was some mood elevation, but with feelings of impaired ability to concentrate. The drug reduced appetite and weight. A comparison is drawn with imipramine, which was found to induce initial and withdrawal changes of subjective experience (of dreaming) in six volunteers. It is suggested that certain mood-influencing drugs may not be drugs of abuse because of some unpleasant initial effects, though they can be drugs of dependence.

In a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without, over 97% of 1,369 mothers took prescribed drugs and 65% self-administered drugs. Significantly more mothers of infants with congenital abnormalities took aspirin, antacids, dextroamphetamine, phenobarbitone, sodium amytal, other barbiturates, cough medicines, iron, sulphonamides, and nicotinamide than mothers in the control group. However, most mothers taking analgesics, antacids, appetite suppressants, barbiturates, cough medicines, iron, sulphonamides, and vitamins produced normal infants. Any teratogenic effect of these drugs is therefore one of low potency. On the other hand, deficiencies such as those of ascorbic acid and folic acid may have a teratogenic effect. There is need for caution in presuming teratogenic effects on the basis of the associations shown here. During pregnancy, however, it would appear wise to avoid the administration of any drug which carries a suspicion of teratogenicity unless that drug is specifically indicated, and self-medication with common household remedies such as aspirin and antacids should be avoided. These recommendations would also apply to any woman of childbearing age in whom conception is likely.

Eight males were studied during 27 weeks, including two periods of five weeks during which they received clinical doses of sodium amylobarbitone and benzoctamine. Substitution of placebo for either drug caused raised anxiety and impairment of mental concentration. The drugs reduced restlessness during sleep and reduced paradoxical sleep. By the fifth week of sodium amylobarbitone, although sleep was still less restless in the early night it was more restless than normal in the late night. Blood samples were taken half-hourly during sleep by indwelling venous catheter. Plasma growth hormone concentration was little affected during drug administration but rose temporarily after withdrawal. There was a reduction of plasma corticosteroid concentration during sleep throughout administration of the drugs and a rebound above normal during the first withdrawal week.

1. The fate of orally administered (14)C-labelled l-alpha-methyldopa has been examined in three normal men and in eight hypertensive patients who responded to the drug and three who did not. 2. The output of (14)C in the urine in 2 days and in the faeces in 4 days was not very different in any of the subjects. The normals excreted about 40% of the dose in the urine and 60% in the faeces, the responders 52% (range 35-60%) and 45% and the non-responders 42% and 41%. Most of the urinary (14)C radioactivity was eliminated in 24h after dosing. 3. The main metabolite in the urine was free and conjugated alpha-methyldopa (normal men, 23%; responders, 37%; non-responders, 25% of the dose). Free and conjugated 3-O-methyl-alpha-methyldopa was about 4% in all subjects, total amines (alpha-methyldopamine and 3-O-methyl-alpha-methyldopamine) about 6% and ketones (mainly 3,4-dihydroxyphenylacetone) about 3%. 4. The output of alpha-methyldopamine (2-4% of dose), 3-O-methyl-alpha-methyldopamine (0.3%) and 3,4-dihydroxyphenylacetone (3-5%) was similar in the one normal and two responders examined. 5. The faecal (14)C in all subjects was unchanged l-alpha-methyldopa. 6. In general, the amounts of the metabolites in the urine in normal men and in responding and non-responding patients were quantitatively similar, except in one non-responding patient who converted nearly two-thirds of the absorbed drug into amines and ketones. There appeared to be no correlation between metabolites in the urine and response or lack of response to the drug. 7. In two normal subjects 70-80% of d-alpha-methyldopa was excreted unchanged in the faeces. Of the absorbed compound most (9-14% of the dose) was excreted as the free and conjugated drug together with a small amount (1-2%) of 3-O-methyl-alpha-methyldopa. No amines and only traces of ketone were excreted.

Plasma levels of tricyclic antidepressant drugs vary considerably between individuals receiving the same amount of drug. The bearing of this variation on the occurrence of subjective side effects was investigated in 40 psychiatric inpatients with depressive disorders. Plasma levels were determined before and during four weeks of treatment with nortriptyline 50 mg. three times a day and patients were rated for subjective side effects, the assessors being unaware of the plasma levels of the drug.Plasma levels varied widely between individual patients, but in any given patient the plasma level tended to be constant over a period of time. The side effects of nortriptyline diminished significantly with time and were in most cases absent during the fourth week of treatment. There was a significant positive correlation between plasma level of nortriptyline and subjective side effects.The steady-state plasma level of a drug which is metabolized is usually a more important determinant for its effect than dosage, since it reflects the amount of drug available for biological action. Very high plasma levels of nortriptyline should presumably be avoided, since there is no evidence that they are needed for therapeutic effect and they are potentially harmful.

1. In the rat, [14C]phenglutarimide HCl was completely absorbed from the gastrointestinal tract and totally excreted in the urine within 24 h after dosing. The drug was not metabolized.2. [14C]Phenglutarimide was widely distributed throughout the body of the rat but only very low levels of radioactivity were detected in the brain. In pregnant animals the drug traversed the placenta and radioactivity was detected in the foetus and amniotic fluid in concentrations higher than or similar to those in the maternal plasma.3. On absorption from the gastrointestinal tract, the drug was rapidly excreted into the urine and consequently tissue levels were low.4. In man, after oral administration of non-radioactive phenglutarimide, the drug was excreted completely in the urine as the unchanged compound within 24 h after dosing.5. In mice, phenglutarimide inhibited the peripheral but not the central actions of oxotremorine, an observation in accord with the distribution pattern of the drug in the rat.6. Phengl...

Fifty patients with exacerbations of chronic bronchitis were treated with either a combination of trimethoprim 320 mg. and sulphamethoxazole 1,600 mg. a day or ampicillin 2 g. a day. The trial, carried out as a single-blind procedure, showed that the combination was more effective as judged by clinical response and reduction in sputum volume and purulence, with eradication of pathogenic organisms. No appreciable side-effects were encountered with either treatment, and it is suggested that the trimethoprim-sulphamethoxazole combination may be a safe and useful drug in the treatment of chronic bronchitis.

Not much is known about the feasibility or the advantages of treatment of subjects with only mild hypertension. There are also many unresolved problems in the outpatient management of hypertension of any severity. In this study an analysis is made of the results of a controlled treatment trial of 56 subjects with mild hypertension, 26 of whom were treated with active drug and 30 initially with placebo, and a treatment programme involving 81 patients with moderate or severe hypertension, all of whom received treatment with active drug. The drugs used in this study were bethanidine, debrisoquine, and guanethidine. Follow-up for 12 months or more was achieved in 87% of individuals admitted to the study with mild hypertension and in 80% with severe hypertension. Many subjects with only mildly raised blood pressure were found to have cardiac enlargement on chest x-ray (up to 45%) and left ventricular hypertrophy on electrocardiogram (up to 51%). Rapid rates of rise of blood pressure were observed in many placebo-treated subjects; but good blood pressure control was achieved in 63 out of 104 patients (61%) receiving active drug in both the mild and the severe hypertension groups. The drugs used showed approximately equal effectiveness in controlling blood pressure.

1. The metabolic fate of 3,5-diiodo-4-(4′-acetoxy-3′-[125I]iodophenoxy)-benzoic acid was studied in rats and its principal metabolites identified.2. The drug, orally administered, was rapidly and almost quantitatively absorbed from the intestine, and was distributed to liver and kidney. Blood levels of radioactivity reached a plateau 3 to 5 h after administration, and gradually decreased. Radioactivity was rapidly excreted, largely in the bile, and entered into entero-hepatic circulation. Subsequent excretion in faeces and urine, amounted to 60 and 25%, respectively, within 72 h.3. Repeated oral administration of the drug did not show any accumulation, except in the thyroid gland, which showed a concentration five times higher than that after a single administration.4. The metabolic fate of the drug in animals receiving a subtoxic dose of the unlabelled drug for 4 weeks did not significantly differ from that in control animals.5. The faecal metabolite was identified as the deacetylated drug. Glucuronide a...

1. The metabolic fate of [3H]terbutaline has been investigated in rats after oral, subcutaneous, intraperitoneal and intraportal administration (5 mg per kg).2. About half the administered radioactivity was excreted in the urine and the remainder in faeces regardless of route of administration. Urinary excretion was essentially complete in 24 h, but an additional 10% of the dose was excreted in the 24–48 h faeces.3. Only one metabolite, a glucuronide conjugate of terbutaline, was excreted in the urine along with unchanged drug. About 3% of the dose was excreted unchanged in urine following oral administration. Ratios of terbutaline glucuronide to free drug were 1 : 1, 2 : 1 and 13 : 1 after subcutaneous, intraperitoneal or intraportal, and oral administration respectively, suggesting that the orally administered drug is extensively conjugated in the intestinal mucosa.4. Measurement of the mobility-pH profile by high-voltage paper electrophoresis was utilized to characterize the conjugate.

Acute pancreatitis is a serious disease with a high mortality. The application of general medical and surgical measures such as intestinal decompression and the correction of dehydration and electrolyte imbalance has reduced this mortality signi ficantly, but more specific therapeutic measures are needed. The most widely accepted theory for the causation of acute pancrea titis at the present time is the activation of pancreatic trypsinogen with digestion of the pancreas (Forell, 1962), and the subsequent activation of potent circulatory enzymes, kalli krein and bradykinin, which may account for the severe clinical states found (Thai et al., 1963 ; Forell, 1963). If this theory is correct the possession of a potent non-toxic trypsin and kallikrein inhibitor should assist greatly in the management of this disease. Such an inhibitor was isolated from the parotid gland of cattle by Frey et al. (1950), and is now marketed as Trasylol, a polypeptide of low molecular weight capable of intravenous or intraperitoneal administration with few side effects. This drug has potent antitryptic activity in vitro (Moshal et al., 1963), and has been shown to be capable of preventing the development of experimentally induced pan creatitis in animals (McHardy et al., 1963 ; McCutcheon, 1963, 1964). However, despite widespread use in acute pancreatitis in humans it is still not possible to determine its value in the treatment of this disease, as most reports have been of un controlled clinical observations (Maurer, 1961 ; Forell, 1963 ; McHardy et al., 1963 ; Moshal et al., 1963). The only report of a double-blind study is a sentence in a review by Nardi (1963) that he found the drug of no benefit in such a trial, but that his figures were too small for statistical analysis. The purpose of this paper is to report a double-blind study of the use of this drug in acute pancreatitis of all degrees of severity treated in other respects by the usual therapeutic measures.

It is surprising that, so far as we can ascertain, no trial has been reported in which the efficacy of a modern "anti depressive " drug has been compared with that of a combina tion of drugs (dexamphetamine and amylobarbitone) widely used in the treatment of depressive illness before the newer drugs were introduced five or six years ago. Proprietary mixtures of dexamphetamine and amylobarbitone are still advertised as of value in depression, and the lack of any comparative trial is perhaps more surprising when it is remembered that the basic cost to the National Health Service of a week's treatment with the ingredients of such mixtures (dexamphetamine sulphate 5 mg. and amylobarbitone sodium 50 mg. t.i.d.) is 5d., while that of the currently most popular antidepressant (imipramine hydrochloride (" tofranil ") 50 mg. t.i.d.) is about 11s. 6d. In this paper we report a controlled comparative trial of imipramine and a proprietary mixture of dexamphetamine and amylobarbitone ("drinamyl"), in the treatment of depressive illness.

Plasma levels of practolol were measured in advanced chronic renal failure. The plasma half life was found to be markedly prolonged. During haemodialysis considerable shortening of the half life occurred. Therapeutic blood levels of practolol can be achieved in maintenance haemodialysis patients by the administration of 200 mg of the drug by mouth at the beginning and end of each dialysis.

A retrospective survey of women treated in prison for trichomonal vaginitis with metronidazole showed that 488 of 496 (98.3%) were cured after one course of drugs. Five of the eight treatment failures were successfully treated by further courses of metronidazole.A regimen of 400 mg metronidazole twice daily for seven days is simple and effective when taken in prescribed dosage. Metronidazole is still the drug of choice for trichomonal vaginitis. No toxic reactions were observed and there was no evidence that the drug has lost efficacy in the last ten years.

In 13 patients with allergic asthma disodium cromoglycate protected fully only two from an allergen-induced asthmatic attack. Inhalation of disodium cromoglycate did not improve lung function in five patients with long-standing chronic asthma. Previous clinical trials do not show convincing evidence that this drug improves bronchial asthma in a high percentage of cases, but it seems to help a small minority of patients.

In an initial trial of glibenclamide in the treatment of maturity onset diabetes mellitus 28 patients were treated for up to one year and no toxic effects or side-effects were encountered. The hypoglycaemic potency of this drug is such that 5 mg. of glibenclamide corresponds to about 1,500 mg. of tolbutamide and 375 mg. of chlorpropamide.

Liver histological appearances were studied in 44 patients treated for psoriasis with methotrexate. Cirrhosis was found in six and hepatic fibrosis in another 11. Of these 17 patients 12 had received methotrexate by a regimen of frequent small dosage, two had been treated by a regimen of intermittent large dosage, while three had been treated at different times by both methods. The prevalence of cirrhosis and fibrosis was significantly greater in patients treated by frequent small dosage than in those treated by intermittent large dosage, though the dose level (mg/month) was similar in both groups. Hepatic fibrosis, sometimes preceding cirrhosis, seems to develop invariably if treatment with small frequent dosage is sufficiently prolonged. In the few circumstances in which this drug is indicated for psoriasis intermittent large dosage is the treatment regimen of choice.

Long-term antibacterial therapy with the drug combination trimethoprim-sulphonamide has been used for the treatment of 52 patients with persistent or recurrent bacteriuria. Hypersensitivity or gastrointestinal intolerance was observed in six. Bacteriuria was controlled in 36 out of 38 patients with organisms sensitive to trimethoprim-sulphonamide, 28 having received treatment for periods ranging from 6 to 49 months. Treatment was in some cases curative and in others suppressive or prophylactic. The importance of supportive measures is re-emphasized.

The results are reported of a preliminary trial of P1496, a new non-steroidal oestrogen analogue, compared with a conjugated equine oestrogen and a placebo. The oestrogenicity of both substances was well substantiated by vaginal epithelial maturation indices. P1496 was superior to conjugated equine oestrogen in producing a significant reduction of plasma calcium levels and a possible reduction in serum cholesterol. Conjugated oestrogen caused slightly more nausea than P1496 but there were no notable side effects from either drug. P1496 is considered to be at least as effective an oestrogenic substance as conjugated oestrogen and worthy of further therapeutic evaluation.

The results of treatment of 25 patients admitted from psychiatric institutions indicate that diazepam is the drug of first choice in the treatment of status epilepticus. The dangers of treatment appeared to result from combined use with other drugs. Respiratory depression occurred in one patient and hypotension in five patients, all of whom had been given intramuscular phenobarbitone in addition to intravenous diazepam. The two serious cases of hypotension had also been given parenteral paraldehyde.

The rate of paracetamol absorption depends on the rate of gastric emptying. Propantheline delayed gastric emptying and markedly slowed the absorption of paracetamol in six convalescent hospital patients. Conversely, the absorption of paracetamol in five healthy volunteers was accelerated by metoclopramide, a drug which stimulates gastric emptying. The total 24-hour urinary excretion of paracetamol was not influenced by propantheline or metoclopramide. Other similar absorption interactions probably occur since drugs are poorly absorbed from the stomach and many therapeutic agents influence gastrointestinal motility.

Co-trimoxazole (trimethoprim-sulphamethoxazole) causes a decrease in the uptake of labelled thymidine in lymphocytes cultured in the presence of phytohaemagglutinin. This phenomenon was observed in 60% of 25 subjects. In cultures affected by the drug the mean suppression was 84%. A small decrease in thymidine uptake was noted with trimethoprim and sulphamethoxazole separately, but the effect was much more pronounced with the combination of the two drugs. The mechanism responsible for this phenomenon is discussed. The action is probably not due to the ability of these drugs to interfere with folic acid metabolism and it is likely that there is no direct effect on DNA synthesis.The suppression of thymidine uptake by lymphocytes in vitro in the presence of co-trimoxazole may not have any obvious clinical significance. However, in view of a report of an immunosuppressive action of trimethoprim in mice, it is possible that the leucopenia observed in some patients treated with this drug may have been caused by a similar mechanism.These experiments show that lymphocytes in vitro are suppressed by co-trimoxazole in concentrations comparable to, or smaller than, those found in vivo under normal therapeutic conditions. They are therefore likely to be clinically relevant.

A clinical and metabolic study of 32 patients treated with glibenclamide for a period of about one year confirmed that the drug is a potent stimulator of insulin release in maturity onset diabetes, and glibenclamide continued to have this action after a period of eight months. The drug is effective in doses as low as 2.5 mg., and the maximum effective dose is about 15 mg. No significant side-effects were found during the period of the study, in particular there was no alcohol flushing. The metabolic investigations have shown that the drug has some actions which are as yet unexplained.

Benorylate (4-acetamidophenyl 2-acetoxybenzoate) is a new esterified aspirin preparation whose antirheumatic properties are reported to be as good as those of aspirin. Gastrointestinal blood loss, measured with (51)Cr-labelled red cells, during benorylate therapy was compared with that during therapy with soluble aspirin in 15 subjects, a simplified crossover procedure being used. Mean blood loss during benorylate therapy was 1.7 ml/day which was significantly less than that during therapy with soluble aspirin (5.1 ml/day; P

Acetohydroxamic acid has been identified, by paper chromatography, in the blood of three patients with chronic myelogenous leukemia on hydroxyurea therapy. This suggests that the drug is hydrolyzed yielding hyroxylamine, which then cleaves thioesters, in particular acetyl-coenzyme A.