The plasma concentrations of ranitidine after oral and intravenous administration have been measured in 10 healthy young adults, nine cirrhotic patients, and eight healthy elderly people. In the first of these bioavailability was 51 +/- 4% and half life 161 +/- 11 minutes after oral and 124 +/- 5 minutes after intravenous administration. In the cirrhotics bioavailability was increased to 70 +/- 7%, clearance was reduced, and there was a modest increase in half life. In the elderly bioavailability was similar to that in young adults, clearance was markedly reduced, and half life was prolonged to 241 +/- 7 minutes after oral and 194 +/- 11 minutes after intravenous administration. It is predicted that blood levels in cirrhotics and the elderly would be 50 to 60% higher than in healthy young adults after repeated oral administration of similar doses.

Altogether 406 infants with neural tube defects born in Cardiff between 1956-71 were investigated for evidence of space-time clustering and 100 similarly affected infants, together with matched controls born in Cardiff between 1964-66 were investigated for evidence of spatial clustering. No evidence of excessive prevalence in either dimension was observed.

The antihypertensive properties of the new diuretic tienilic acid were investigated. Thirteen previously untreated hypertensive patients took part in a double-blind crossover study in which 30 days' treatment with tienilic acid 250 mg, bendrofluazide 5 mg, and spironolactone 100 mg were compared. Bendrofluazide caused the greatest natriuresis on the first treatment day and the most rapid fall in blood pressure. The ultimate antihypertensive effect of all three drugs was similar. Tienilic acid caused a noticeable reduction in serum urate concentrations and a rise in urate clearance, in contrast to the other two agents, which caused slight urate retention. Tienilic acid and bendrofluazide caused falls and spironolactone a rise in plasma potassium concentrations. No untoward effects were seen from any of the drugs. It is concluded that tienilic acid is a moderately potent diuretic that lowers plasma urate concentrations. It may be the drug of first choice for hypertensive patients who already have gout or are likely to develop it when taking thiazide diuretics.

The frequency of dicentrics + ring (dic/cell) and total chromosome aberrations (dicentrics, rings and excess acentrics, etc.) per cell (TAb/cell) has been studied in 50 male and female volunteers after high or low dose rate (HDR, LDR) irradiation of peripheral blood lymphocytes. The mean male aberration frequencies per cell after HDR irradiation were 0.38 dic/cell and 0.61 TAb/cell; following LDR irradiation, the mean aberration frequencies were 0.28 dic/cell and 0.45 TAb/cell. Equivalent female values after HDR irradiation were 0.42 dic/cell and 0.71 TAb/cell; after LDR irradiation, the mean aberration frequencies were 0.30 dic/cell and 0.48 TAb/cell. Analysis of variance showed that there was a highly significant difference between males and females have a greater HDR, but not LDR, irradiation It is concluded from this study that females have a greater variability in their radioresponse, and that this variability is related to progesterone, which has a profound effect upon radiosensitivity, as measured by cytogenetic end points.

The expression of thymidine kinase in fungi, which normally lack this enzyme, will greatly aid the study of DNA metabolism and provide useful drug-sensitive phenotypes. The herpes simplex virus type-1 thymidine kinase gene ( tk ) was expressed in Neurospora crassa. tk was expressed as a fusion to N.crassa arg-2 regulatory sequences and as a hygromycin phosphotransferase-thymidine kinase fusion gene under the control of cytomegalovirus and SV40 sequences. Only strains containing tk showed thymidine kinase enzyme activity. In strains containing the arg-2 - tk gene, both the level of enzyme activity and the level of mRNA were reduced by growth in arginine medium, consistent with control through arg-2 regulatory sequences. Expression of thymidine kinase in N.crassa facilitated radioactive labeling of replicating DNA following addition of [3H]thymidine or [14C]thymidine to the growth medium. Thymidine labeling of DNA enabled demonstration that hydroxyurea can be used to block replication and synchronize the N.crassa mitotic cycle. Strains expressing thymidine kinase were also more sensitive than strains lacking thymidine kinase to anticancer and antiviral nucleoside drugs that are activated by thymidine kinase, including 5-fluoro-2'-deoxyuridine, 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouridine and trifluorothymidine. Finally, expression of thymidine kinase in N. crassa enabled incorporation of bromodeoxyuridine into DNA at levels sufficient to separate newly replicated DNA from old DNA using equilibrium centrifugation.

There is an important distinction between worth and affordability which remains largely unrecognized. It is widely supposed that if an economic analysis shows that the benefits of a service exceed its costs, failure to fund it is irrational and inefficient. By means of a simplified model of a health care system, it is shown that although an excess of benefits over costs is a necessary precondition for providing a service, it is by no means sufficient. If society is to make the best use of its resources in health care, worthwhile services--those which make a social 'profit'--must be compared with other such services. Since the resources available to any health care system will always be limited, it is likely that not all services whose benefits exceed their costs can be afforded, because the budget has already been committed to those worthwhile services which yield higher benefits per unit cost.

A case is described of the rare syndrome of recurrent idiopathic pneumomediastinum which had been mistakenly diagnosed as recurrent spontaneous perforation of the oesophagus. The case illustrates the importance of distinguishing between pneumomediastinum and oesophageal rupture because of their markedly differing prognosis and management.

Images

The effect of cimetidine on normal human gastric mucus has been compared with that of carbenoxolone, a drug believed to enhance mucus production. Each drug was given for two weeks, the gastric contents aspirated over a timed period and the results assessed in unstimulated and pentagastrin stimulated secretions. The volume, dry weight and the carbohydrate contents of non-diffusable glycoconjugates, high molecular mass glycoproteins and glycopolypeptides were investigated. Both drugs reduced the volumes of stimulated secretions. This was statistically significant after cimetidine. More importantly neither drug affected the amount of non-diffusable glycoconjugates, so that the concentration remained the same or increased. Both drugs reduced the monosaccharide content of the high molecular mass fractions. This reached significance for the stimulated secretion after cimetidine. As the carbohydrate content of the glycopolypeptides was unchanged this indicated the presence of a non-mucin glycoprotein or protein. Overall there was no fundamental difference between the results for cimetidine and carbenoxolone.

The efficiency of the selection of patients with injured arms and legs for radiography was investigated. The analysis was based on data on presenting signs and symptoms collected in a multicentre study organised by the Royal College of Radiologists working party on the effective use of diagnostic radiology. The work was carried out in eight accident and emergency units in England and Wales. With the help of various computer simulation techniques a combination of signs and symptoms that might usefully improve present practice was sought. The results suggest that for injuries of arms and legs the clinical determinants of bony injury cannot be refined further to improve current selection for radiography. This study shows that existing clinical practice is probably as good as it can be.

As part of an investigation into the practical problems of a maternal serum alphafetoprotein (AFP) neural tube defect (NTD) screening programme carried out in Mid Glamorgan, South Wales, between 1977 and 1979, obstetricians were recommended to refer women with high risk pregnancies directly for counselling, high resolution ultrasonography, and amniocentesis without first carrying out serum screening. Out of 15 687 pregnant women one-third attended too late to be screened. A total of 637 was classed as high risk, mostly at greater risk than 1 in 50 because of a previously affected pregnancy or an affected close relative. Compliance with recommended procedure was relatively low as many were screened. There were 10 pregnancies with a recurrence of NTD, of which one was not tested at all, two were not detected (one closed meningocele and one closed iniencephalic), and seven were detected and the pregnancies terminated. All the latter, as well as the iniencephalic, would have been detected from a serum AFP determination and a high resolution ultrasound scan alone. It is concluded that these investigations are sufficient for high risk pregnancies and that amniocentesis is not really cost effective or necessary unless either of these investigations is abnormal. As numbers in this study were small it is suggested that these conclusions should be tested in a larger study.

Clinical and financial gains and losses accruing from five different options for screening for open neural tube defects were estimated, based principally on the results of detailed monitoring of inputs and outcomes and of process costs in the South Wales Anencephaly and Spina Bifida Study. As well as estimating the overall clinical costs of a screening service it was shown that if the prevalence, including terminations, of open neural tube defects is between 1.25 and five per 1000 births the financial cost of avoiding the birth of a seriously handicapped child who would survive for more than 24 hours is in the range 9000 pounds- 54000 pounds depending on the option adopted and the prevalence of the condition in the target population. Prevalence is the biggest determinant of cost. The data should provide a basis for assessment and discussion of resource priorities in the National Health Service.

A patient is reported who developed a hitherto unrecognized drug interaction between azapropazone and anticonvulsants which led to toxicity with the latter. The mechanism of this interaction is discussed.

Cimetidine 200 mg three times daily and 400 mg at night was given to 10 subjects for four weeks. Apparent liver blood flow was measured by indocyanine green clearance and microsomal enzyme activity by antipyrine clearance, before and after cimetidine. There was no reduction in indocyanine green clearance but antipyrine clearance, as expected, was significantly reduced by 15% at four weeks. Chronic cimetidine treatment does not reduce apparent liver blood flow and is therefore unlikely to be of use in the treatment of portal hypertension. The cimetidine associated hepatic enzyme inhibition appears to persist with prolonged treatment. Therefore patients on chronic cimetidine remain vulnerable to certain drug interactions.

This paper takes as an example of the cycle of evaluation the work of the Royal College of Radiologists in connection with the more effective use of preoperative chest X-ray. The work covers a six year period beginning with an observation of practice on a national sample in 1976, progressing to the comparison of existing practice with expectations in 1978. This was followed by the development of guidelines of practice which were disseminated informally, and formally through scientific papers and meetings from 1979. In 1981, practice was again observed in a pilot area to ascertain if the proposed guidelines had produced the desired affect. The results of this second review showed that the intentions of the guidelines had been achieved successfully, i.e. substantial reduction in utilization with considerable potential financial saving without any decrease in the original effectiveness or safety of the intervention. Thus this example shows the closing of the evaluation loop and the successful implementation of change.

The pharmacokinetics of metronidazole 500 mg orally were determined in patients with hepatosplenic schistosomiasis and normal controls in the Sudan, and in cirrhotics and normal controls in Bristol. Plasma metronidazole levels were above the minimum inhibitory concentration of most susceptible anaerobic bacteria for four to six hours post-dose in all groups. Liver disease did not markedly influence the disposition of single oral doses of metronidazole. Cirrhotics showed some prolongation of metronidazole half-life, and somewhat greater metronidazole concentrations 24 hours after the dose. Concentrations of the oxidative metabolite of metronidazole were lower in Sudanese patients and normal controls than in normal British subjects. In chronic liver disease adjustment of metronidazole dosage is probably not required provided renal function is unimpaired.

Liver size has been estimated clinically and by a non-invasive ultrasound technique in 16 normal subjects, 16 patients with cirrhosis, 10 patients with chronic biliary obstruction, and three patients with primary hepatoma. Antipyrine disposition was also measured in each subject. Hepatomegaly was not clinically detectable until there was approximately a 20% increase in liver size. Additional increases in size correlated significantly with clinical estimates of hepatomegaly. Antipyrine clearance had a three-fold range in normal subjects. Its mean value was significantly reduced in each subgroup of patients with liver disease. However, 48% of patients with liver disease had values within the normal range. In normal subjects there was a significant correlation between antipyrine clearance and liver volume. Thus, intersubject variation in clearance normalised for liver volume was less than clearance alone. Antipyrine clearance normalised for liver volume in patients with liver disease was significantly lower than in normal subjects and there was no overlap with normal subjects. In conclusion, assessment of drug metabolising efficiency per unit volume of liver increased the discrimination in differentiating subjects with normal from abnormal livers.

The interpretation of maternal serum alpha-fetoprotein (AFP) concentrations in relation to fetal neural tube defects depends on accurate assessment of the gestational age. In a quadruple-blind study three antenatal methods of assessment--namely, menstrual dates, clinical examination, and ultrasound scanning--were correlated with postnatal assessment using the Dubowitz scoring system. The best agreement to +/- 1 week was obtained using menstrual dates and ultrasound in combination, such agreement being found in 91 (77%) of the 118 women studied. Since serum AFP concentrations vary with gestational age, precise gestational dating is necessary. In many cases, particularly in women who are unsure of their dates or have irregular menstrual cycles, ultrasound examination is needed to supplement clinical findings.

The effect of malnutrition on hepatic drug-metabolising enzymes was investigated in 8 Sudanese children aged between 9 and 12.5 years using as a model the drug antipyrine. Antipyrine half-life and clearance were measured in the malnourished state and after 3 or 4 weeks of good nutrition. Associated with the improvement in nutritional state was a shortening of antipyrine half-life and an increase in its clearance. There was also a rise in serum triiodothyronine. It is concluded that poor nutrition is associated with impairment of drug metabolic capacity and that many factors are responsible.

The effect of chronic liver disease on the rate of elimination and extent of "first-pass" metabolism of labetalol was studied. Pharmacokinetic measurements were made after both oral and intravenous administration to seven healthy subjects and to 10 patients with chronic liver disease. Plasma half life was similar in the two groups. Plasma concentrations were considerably higher in the patients than in the healthy subjects after oral administration but similar after intravenous injection. Thus the bioavailability of labetalol was increased in liver disease due to reduced first-pass metabolism. Bioavailability in the group of patients correlated negatively with serum albumin concentration. There were falls in supine heart rate and blood pressure which tended to be greater after oral administration in the patients with liver disease, suggesting an exaggerated response related to the increased bioavailability. Oral dosage requirements of labetalol and possibly other drugs susceptible to first-pass metabolism are reduced in the presence of liver disease.

The marriage-to-conception interval in 151 pregnancies producing infants with anencephaly or spina bifida was not significantly different from that in 218 pregnancies resulting in normal infants. Significantly more miscarriages occurred before than after the birth of 285 infants with anencephaly or spina bifida, but in 133 controls no before-after difference was observed. These observations seem to favour the idea that miscarriages are a manifestation rather than a cause of anencephaly and spina bifida.

A case is described of the death of a young female patient following the administration of a salt emetic after a relatively minor overdose of a proprietary analgesic containing aspirin. It is suggested that death occurred as a direct consequence of the salt ingestion and that the dangers of this method of inducing emesis should be more widely appreciated.

Fibre-optic endoscopy was compared prospectively with double-contrast radiology in 53 consecutive patients admitted with acute gastrointestinal haemorrhage. The bleeding site was correctly identified by endoscopy in 94% of patients and the final diagnosis was correctly given in 89%. The corresponding figures with radiology were 83% and 74%. Among the 50 patients with a final diagnosis of a bleeding site in the upper gastrointestinal tract endoscopy indicated the site of bleeding in all and radiology indicated it in 88%. Both investigations were well tolerated by patients. Endoscopy is the investigation of choice, but when it is not available double-contrast radiology will show the site of bleeding in 80-90% of patients.