Influenza and the work of the World Health Organization.

Before World War I, influenza was not considered a particularly serious problem. The great pandemic of 1918-1919 changed all that, and the possibility that such a catastrophe could occur again has conditioned all subsequent developments. In epidemiological terms, the hallmark of an influenza is the excess mortality that it causes combined with an enormous burden of ill-health that saps the energy of individuals, families and communities throughout the whole world. In order to engage in influenza prevention and control, the global influenza surveillance network was set up by World Health Organization (WHO) in 1948 as a worldwide alert system for the identification of new influenza viruses, gathering information from 110 participating laboratories in 82 countries and four WHO Collaborating Centers for Influenza reference and research: Centers for Disease Control and Prevention, Atlanta (USA), National Institute for Medical Research, London (UK), WHO Collaborating Centre for Influenza Reference and Research, Melbourne (Australia) and the National Institute for Infectious Diseases, Tokyo (Japan). This network helps WHO to monitor influenza activity all over the world and provides the organization with the viral isolates and information it requires to decide which new virus strains will be used to produce influenza vaccines during the following season. Each year, information about the isolates over the previous 12 months is analyzed and used to determine the composition of the influenza vaccine to be administered during the coming influenza season both for the northern and southern hemisphere. If necessary, the recommendations for the southern hemisphere differ from the ones formulated for the northern hemisphere vaccine. The information supplied by this network enables the organization to regularly update its World Wide Web (WWW) site (FluNet), which reports on the situation of diseases. This network will also enable the WHO to detect a new influenza pandemic as early as possible.

Estimate of the global market for rifampicin-containing fixed-dose combination tablets.

SETTING: Despite WHO and IUATLD recommendations to use fixed-dose combination (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used in the public sector globally is administered as single drug tablets. OBJECTIVE: To estimate the potential global market for rifampicin-containing FDCs in the public and private sectors. DESIGN: The public sector market for FDCs was calculated from the number of tuberculosis cases notified to WHO for 1996 and from information on treatment regimens currently used in each country. The private sector market was calculated from the estimated number of treated tuberculosis cases and the treatment regimens presumed to be used in the private sector. RESULTS: The potential global market for the four-drug FDC tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg) is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200 (90%CI 95-345) million of which would be distributed in the public and private sectors, respectively. The uncertainty of the estimate remains considerable, as shown by the 90% confidence intervals. CONCLUSION: The study demonstrated a large potential global market for FDCs that should encourage pharmaceutical manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

Availability of quality fixed-dose combinations for the treatment of tuberculosis: what can we learn from studying the World Health Organization's vaccine model?

SETTING: In efforts to promote the use of fixed-dose combinations (FDCs) for the treatment of tuberculosis (TB), the World Health Organization (WHO) and partners address the issue of quality assurance. OBJECTIVE: To provide guidance for the development of strategies for quality assurance of FDCs. DESIGN: This review examines the WHO strategies for and experience with quality assurance and supply of vaccines. RESULTS: Several elements in the strategies for quality assurance and supply of vaccines may be applicable for FDCs. At national level, the important strategies are to strengthen National Regulatory Authorities (NRA) and procurement systems and develop planning activities. Stressing quality assurance of FDCs in training activities for regulatory personnel and recommending that aid agencies require adherence to quality assurance policies as conditions for support would promote the implementation of quality assurance of FDCs at country level. At the global level, pre-qualification of manufacturers of FDCs should be explored as a mechanism to assure quality. The pre-qualification process should include evaluation of product files, initial testing for compliance and consistency of specifications, and site visits to producers and NRAs. The vaccine model defines criteria for reassessment that can be used for FDCs.

The changing face of hypertension and antihypertensive agents.

In summary, much is needed to be done to foster thinking, both by patients and healthcare providers, in terms of disease risks and benefits of medical care, including those of pharmaceutical options. Healthcare professionals have been relatively ineffective patient educators, perhaps because there is still the old paternalism of 'doctor knows best'. Also, insufficient attention has been given to enhance the communication skills of healthcare professionals. Very likely, one of the reasons is the pressure to control costs which limits the time that healthcare professionals spend consulting with patients. Less than ideal compliance has even been reported in large-scale trials. For example, in the SHEP trial, a 90% compliance was reported (perhaps because of patient selection) but in the Studies of Left Ventricular Dysfunction (SOLVD), only 80% compliance was achieved. Poor adherence to long term treatment, both lifestyle modifications and pharmacological therapy, has been identified as the major reason for inadequate control of elevated BP; some sources claim that only 25% of all hypertensive patients have controlled BP. Thus planned patient education efforts should be undertaken as these can significantly improve BP control and decrease hypertension-related morbidity and mortality. To achieve this, the patient must become an active participant in the planned regimen, and not remain a passive recipient (table III).

Clinical trials and transethnic pharmacology.

It is generally agreed that the advance of a global economy must be accompanied by global drug development. Thus, more intense effort, time and expense must be given to the study of overall global population, which will ultimately be exposed to the drug in development. Race and ethnicity of the ultimate drug consumer must be evaluated, and not only in broad terms. Ethnic and racial representations must be considered in clinical trials. The differences in response to drug action in various ethnic and racial groups must be evaluated to provide information for the physician in practice, who is faced with an increasingly nonhomogeneous population, and who must prescribe medications for those patients. The practising physician urgently requires international, crosscultural collaborative studies, using standardised methods applicable to different cultural settings.

Coronary disease: are there gender differences?

Prevalence rates from hypertensive heart disease are higher for women, while men have higher prevalence rates for coronary heart disease. Female gender is associated with increased mortality after acute MI. Females have also been shown to respond differently to men to a host of approaches to CHD. Both surgical and pharmacological interventions appear to be less effective in females than in males. Answers are still needed, but they have not been forthcoming because, in general, inadequate numbers of females were included in most applicable clinical trials. It may be that males are over-treated rather than that females are under-treated. It is incorrect to extrapolate findings in men to women, given the differences. Studies are needed to determine what intervention strategies in the primary prevention and treatment of coronary disease should be used for women and the elderly.

Elderly hypertensives and quality of life: some methodological considerations.

Management of mild hypertension in the elderly aims at symptom relief and a change in the natural history of hypertension. This is often difficult, since mild hypertension is generally symptomless but drug therapy may have serious quality of life sequelae. Therefore, aspects of patient well-being, including physical, emotional, and social status, should become important treatment considerations, which can be achieved by a patient-specific approach. Quality of life claims for specific drugs appeal to the desire of the prescriber to use the best drug in real-life situations. Physicians generally are guided in their selection of a particular drug for a particular patient by results of clinical trials. This is still difficult to achieve with quality of life studies pertaining to drug management of mild hypertension in the elderly. Few studies have been done, and some do not yield clear results. One needs to study carefully the duration of the trial, the validation of the instruments used, the approach to confounding factors such as inclusion and stratification of elderly by decade of life, inclusion of females in requisite numbers and prior symptoms of patients who, more likely than not, suffer from a host of intercurrent diseases and have been placed on multiple drugs.

Differences in men and women in coronary artery disease, systemic hypertension and their treatment.

Various studies have shown that women with coronary artery diseases are treated quite differently from men, although the reasons for these differences are not easily discernible and may be based on misconceptions. Furthermore, although the attributable risk percentage for cardiovascular complications of hypertension is higher in women than in men, little information on treating hypertension in women is available. There is cause for concern owing to some findings that white women may be harmed by antihypertensive treatment unless that treatment differs from that of men. Consensus on the importance of this finding has not been reached.

Optimising the economic efficiency of drug studies.

The cost of the development of a new drug product, from concept and synthesis of a new chemical entity to safety and efficacy testing, to the approval process and postmarketing surveillance, has more than quadrupled in the last 20 years. To amortise these costs, the pharmaceutical industry has taken on international dimensions. These efforts will not be enough. This review outlines many cost-saving and cost-containment suggestions that have been instituted or that need to be instituted in order to bring cost-effective drug therapy to individual patients. As the cost of illness continues to increase worldwide, it is imperative that new and cost-effective medications be developed and brought to worldwide markets. This article considers components of the drug discovery and development processes which are likely to be inefficient and correctable. It further reviews current knowledge about the conduct of different parts of the processes, including different types of clinical trials and proposals that have been made to address these in an efficient manner. Documented and proposed cost-containment measures are presented, using several large scale trials as examples. Particular emphasis is placed on statistical methods and their contribution to either efficiencies or inefficiencies. No facet of the drug/product development should be overlooked in the attempt to reduce costs, from reducing the time it takes to bring a product to market to simple but too-frequently occurring errors, such as failing to have trial material at hand at the optimum time.

Preventing postoperative acute bleeding of the upper part of the gastrointestinal tract.

Two hundred and ninety-eight critically ill patients at risk for the development of postoperative stress ulcers and bleeding were randomized into three groups. The first group comprised 85 patients who received meciadanol, a new bioflavonoid, 500 milligrams every six hours through a nasograstric tube; the second group comprised 100 patients who received sucralfate (crushed tablets), 1,000 milligrams every six hours through a nasogastric tube, and the third group comprised 113 patients who received an antacid (Maalox [magnesium aluminum hydroxide gel]) through a nasogastric tube at an initial dose of 15 milliliters every hour. The gastric pH was measured hourly and titrated to a pH greater than or equal to 4.0 in patients in the group receiving the antacid. The gastric pH was measured every two hours in the other two groups. Bleeding in the upper part of the gastrointestinal tract was determined visually (frank blood in gastric contents) or by guaiac testing. Bleeding occurred in seven patients receiving meciadanol, nine receiving sucralfate and six receiving the antacid. The difference in rates of bleeding was not statistically significant. Correlation between the severity of illness index and the development of bleeding was poor, at least in the low and intermediate index range. In contrast, there was a strong correlation between the age of the patient and the development of bleeding. Only one patient younger than 50 years had bleeding develop. Apparently, meciadanol exerts its action by a mechanism other than pH control. It may, therefore, fill an important gap in the ability to prevent postoperative stress ulcers and bleeding.

Clinical trials in hypertension: the present and perspectives for the future.

Testing antihypertensive drugs solely for their efficacy and safety does not meet modern therapeutic demands. Clinicians need to know how drugs behave during an overdose and how they affect a patient's quality of life. In the future, health economists will be involved much earlier and more intimately in the development of trial methodology, to value a drug's contribution to a patient's lengthened life-span and to compare this effect with the drug's potential contribution to society at large. New trial methodologies will evolve, particularly community trials and case-control (phase IV) studies. Since it is now accepted that control of hypertension alone will not prevent development of coronary artery disease, methodologies and experimental design will focus on 13 major and minor risk factors for coronary artery disease, their interplay with hypertension and their possible control with antihypertensive agents.

Clinical trials in the elderly. Pivotal points.

A clinical trial, that is, the scientific assessment of drug action in humans, must be undertaken only if there is reference to an expectation of benefit from the trial. Before the trial starts, a series of questions should be answered, including the need for the trial in elderly patients, particularly in view of the possible vulnerability of the elderly study subjects. Patient selection, randomization, follow-up, analysis, and interpretation must be scientifically valid. Of major importance is the external validity of the trial, that is, the generalizability. Any trial, particularly those involving the elderly, should be designed to develop or contribute to generalizable knowledge; that is, it should be possible to extend the conclusions from the trial beyond the study population to the population at large. When elderly are involved, as they should be when a drug is proposed for use mainly in the elderly population, it is especially important that the study be scientifically valid, medically important, and ethically sound. Studies involving the elderly should have sufficient numbers of females and minorities, the former because most elderly patients are females, the latter because minorities now reach the age of 65 years and beyond more so than in the past. Both risk and benefit should be addressed in terms of potential magnitude and duration. If the study drug has a narrow therapeutic window, it should be intensively studied. When the study is completed, there ought to be clear guidelines for the clinician to design initial, individualized, optimal dosage regimens or for subsequent adjustment of the regimen. The final report, which should be easily evaluable by clinicians, should fully discuss reasons for dropouts, inappropriate patient inclusion, number and types of adverse reactions, and defects in design and conduct of the study.

[Dose-response curve and preliminary clinical study of a laxative, lactilol]. / Courbe dose-réponse et étude clinique préliminaire d'un laxatif, le lactitol.

15 women complaining of chronic constipation were included in a prospective open trial to determine the laxative action and minimal effective dose of lactitol. Through the administration of increasing doses, an ED50 of 0.25 g/kg/day, was established. During a 15-day treatment period at the minimal effective dose, all patients had reduced symptoms of constipation as compared with a previous 15-day control period. Side effects of minor intensity were frequently recorded (flatulence, rumblings, wind, and, less frequently, abdominal cramps or nausea). Thus, the use of lactitol for symptomatic treatment of constipation deserves further clinical studies to determine better its indications and benefit.

The changing face of clinical trials.

We have now seen 20 years of clinical trials testing the efficacy and safety of antihypertensive drugs, involving more than 40,000 patients internationally. Much has been learned and should be applied to future studies. First, patient selection: will selection of patients from different races and nationalities permit pooling of data? There should be a sufficient number of female patients and elderly patients above 80 years of age to draw unequivocal conclusions about the effectiveness of antihypertensive treatment in that population. Further, will the patient population reflect the population cared for by individual community practitioners? End-points must be carefully selected, and it will be important to prove not only that a specific drug can lower blood pressure, but also how far blood pressure should be lowered. Lowering of blood pressure per se is not enough, and end-points should involve all-cause mortality and specific mortalities. Data analysis may revolve around intention to treat analysis or on-treatment analysis. Regarding side effects of the study drug, consideration should be given to survival statistics. Finally, decision analysis is needed. After the trial, postmarketing surveillance is important, and patient selection is just as important in that instance as it was in the original trial. Once the trial has been completed, careful meta-analysis is needed to answer the question still unanswered: can small multiple-centre trials replace large, international trials? One should not consider a trial completed unless measures have been suggested or taken to inform the practising clinician of the inferential statistics applied to the data and the meaning of the data analysis for the clinician in managing the individual patient.

The protective effect of Meciadanol (O-methyl-3(+)-catechin) on experimental ulceration.

Meciadanol, (O-methyl-3(+)-catechin), a histidine decarboxylase inhibitor was shown to have a marked protective action against experimental peptic ulceration in three rat models. The three methods used to induce ulceration were the instillation of absolute alcohol, pyloric ligation following an ulcerogenic South Indian diet and the instillation of rice bran oil into the stomach after pyloric ligation. Meciadanol was shown to reduce incidence, numbers and areas of ulceration and protected mast cells against degranulation and to preserve a normal vascular patterns. Furthermore, Meciadanol reduced gastric acid output and concentration in the pylorus ligation model. These results indicate that Meciadanol may be useful for the treatment of peptic ulcers in humans.

An approach of the in vivo antibacterial activity of benzoxonium chloride and comparison with other buccopharyngeal disinfectants.

Different pharmaceutical forms of N-benzyl,N-dodecyl-N,N-di(2-hydroxyethyl) ammonium chloride (benzoxonium chloride, Orofar) have been tested on the overall buccopharyngeal bacterial count in healthy volunteers, and compared to competitors. Gargle solutions are most effective in reducing initial bacterial count. An open repeated dose study has been performed on 38 patients with sore throat to assess the safety and the efficacy of benzoxonium chloride tablets and gelsolets at doses of 6 mg and 10 mg daily for 4 to 6 days. Pathogens disappeared or were clearly reduced and the syndrome resolved. Tolerance was good. Differences in methodologies are discussed.

Protective effect of methylxanthines against carbachol-induced bronchoconstriction in normal subjects.

The bronchoprotective effect of bioequivalent doses of theophylline (TH; 234 mg) and a combination of TH, proxyphylline (PPH) and diprophylline (DPH) in the proportion 2:3:3 (Neo-Biphyllin, NB; 600 mg) against carbachol-induced bronchoconstriction was studied in 10 healthy non-smokers in a randomised controlled double-blind cross-over trial. The subjects were on a methylxanthine-free diet 4 days prior to and during each study day. Bronchial provocation tests were conducted in the morning and afternoon of the three separate study days--control and two medication days--using a standardised technique. On the control day, the dose of carbachol required to reduce the partial expiratory flow volume at 25% of vital capacity (V25p) by at least 25% was established. A significant protective effect was achieved with both TH (p less than 0.05) and NB (p less than 0.001) as measured by V25p. Bronchoprotection was achieved with low maintenance serum levels of TH.

Gastric protection by meciadanol. A new synthetic flavonoid inhibiting histidine decarboxylase.

Flavonoids reportedly inhibit histidine decarboxylase and reduce gastric mucosal histamine content. We studied the effects of acute and chronic intragastric administration to rats of meciadanol, a new synthetic flavonoid (Zyma S.A., Nyon, Switzerland). The action of meciadanol was compared to that of 16,16-dimethyl PGE2. Meciadanol did not affect acid or pepsin output at any dose used. High doses of 16,16-dimethyl PGE2 reduced both acid and pepsin output. Meciadanol partially prevented aspirin-induced lesions but the prevention required chronic administration of meciadanol. In contrast, a single dose of meciadanol completely prevented ethanol-induced lesions. Chronic administration of meciadanol also completely prevented ethanol-induced lesions. 16,16-Dimethyl PGE2 prevented both aspirin-induced and ethanol-induced lesions in doses that did not affect acid or pepsin output. Meciadanol did not influence the effect that either aspirin or ethanol had on endogenous mucosal PGI2. Thus, the dose range of meciadanol that protected against ulcerogens did not affect either gastric acid secretion or pepsin output. Therefore, we conclude that meciadanol's action represents true cytoprotection, which was previously attributed only to prostaglandins.