A dose-ranging study of labetalol in moderate to moderately severe hypertension.

Labetalol optimal doses for Indonesian patients were investigated in an open, multicentre, unforced titration dose-finding study involving 134 essential hypertensive outpatients with baseline supine DBP (SuDBP) of 105-129 mmHg. Labetalol was started at 50 mg bid and as necessary increased by 50 mg bid every 2 weeks. Evaluable for efficacy were 105 moderate and 25 moderately severe hypertensives. Labetalol was effective (decreased SuDBP to 90 mmHg or less) in 75% of patients and moderately effective (decreased SuDBP at least 10% of baseline but did not reach 90 mmHg) in 10%. The cumulative percent responders were 15, 49, 79 and 85% to final daily doses of 100, 200, 300 and 400 mg, respectively. Adverse reactions were found in 31% of patients, the most frequent were gastrointestinal complaints causing 3 withdrawals. It is concluded that labetalol optimal doses for Indonesian moderate to moderately severe hypertensives range from 100 to 300 mg daily in 2 divided doses.

Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population.

1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin. 2. The mean ( +/- s.d.) values of the elimination half-life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/- 3.1 vs 14.6 +/- 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/- 1.89 vs 3.68 +/- 0.83 (0.58 to 2.91) micrograms ml-1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/- 0.13 vs 0.88 +/- 0.50 (-0.14 to 0.96) micrograms ml-1 h). 4. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = -0.661) and AUC (rs = -0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = -0.876), PG/CPB (rs = -0.833) and PG/(CG + CPB) (rs = -0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Dapsone N-acetylation, metoprolol alpha-hydroxylation, and S-mephenytoin 4-hydroxylation polymorphisms in an Indonesian population: a cocktail and extended phenotyping assessment trial.

We examined dapsone N-acetylation and metoprolol alpha-hydroxylation and S-mephenytoin 4-hydroxylation phenotypings using the respective test probes (dapsone and racemic metoprolol and mephenytoin) administered separately and in a cocktail manner to an Indonesian subject group (n = 30). After ascertaining that the separate and cocktail phenotyping tests of the probe drugs correlated with each other (all rs values > 0.84; p < 0.001), the cocktail phenotyping assessment was extended to the other 74 Indonesians. In a total of 104 Indonesians phenotyped with the cocktail test, a visual antimode was apparent only in the dapsone N-acetylation and S-mephenytoin 4-hydroxylation polymorphisms: the frequencies of slow acetylators and poor hydroxylators were 43.3% (95% confidence interval, 33.7% to 52.8%) and 15.4% (95% confidence interval, 8.5% to 22.3%), respectively. The distribution histogram and probit plots of the metabolic ratio of metoprolol gave no clear evidence for bimodality, and therefore no poor alpha-hydroxylator of metoprolol was considered to exist in the present sample size. The findings indicate that the Indonesian subjects have a greater incidence of slow acetylator phenotype compared with Japanese and Chinese, as well as a frequency of poor metabolizer phenotype of S-mephenytoin similar to that of Korean and Chinese subjects. They resemble an African population (Nigerians) in metoprolol alpha-hydroxylation polymorphism, with no apparent antimode derived from white populations.

The Indonesian Drug Advisory Committee and the drug approval process.

The Indonesian Food and Drug Agency began to evaluate drug applications in the early 1970s through an Advisory Committee. This was in response to the perestroika-like policy applied to our drug industry; nowadays there are more than 300 drug companies formulating some 13,5600 drug products. During 1977-1988, 603 drugs were evaluated by the Advisory Committee; 66% were single drugs and 34% were fixed dose combinations. Nine-hundred and twenty-five sessions were needed to arrive at decisions. Most of the applications (88.5%) were reviewed in one or two sessions but 8 drugs took 6-12 sessions. The time needed for assessment may vary from 1 to 3 months (61%), but some have needed almost a year and a half. There were 60% acceptances for single drugs and 35% for fixed combinations.

A dose-ranging study of phenylpropanolamine on nasal airflow.

A double-blind randomized placebo-controlled study comparing the effect of 2-dose levels of phenylpropanolamine (PPA) for acute rhinitis was performed in 180 outpatients. PPA was given in a fixed dose combination with paracetamol, chlorpheniramine and vitamin C. Two doses of each drug were given with a 4-h interval. Based on objective evaluation of nasal airflow using a Connell rhinometer, it was shown that PPA 25 mg was significantly more effective than the active placebo and PPA 15 mg. The decongestant effect of PPA 25 mg was markedly seen after 1 h, becoming maximal after 1.5 h, and was maintained for 2 h, after which the effect decreased until just before the second dose was given. The second dose gave a similar result as the first dose. PPA 15 mg was less effective and of shorter duration than the 25 mg dose, but gave sufficient improvement of nasal congestion.

Pharmacokinetic and pharmacodynamic properties of controlled release (CR/ZOK) metoprolol in healthy Oriental subjects: a comparison with conventional formulations of metoprolol and atenolol.

The steady state pharmacokinetics and pharmacodynamics of metoprolol controlled release tablets 100 mg CR/ZOK, was compared with those of metoprolol conventional tablets 100 mg (CT) and atenolol 50 mg (ATL) in ten healthy Oriental men. The study was of double-blind, cross-over placebo controlled design. The three study drugs and placebo were given in a random order once daily for 4 consecutive days with 1-week wash-out between each period. Treadmill exercise tests were performed and blood samples were obtained at fixed intervals after the fourth dose of each treatment. There was less fluctuation in the plasma level-time profile after CR/ZOK than CT and ATL. Plasma concentrations were significantly higher on CR/ZOK than CT at 24 hours after dosing. The relative bioavailability of CR/ZOK to CT was 69.0%. CR/ZOK achieved relatively more uniform beta-blocking effect over the dose interval. Compared to CT and ATL, the peak effect after CR/ZOK was less pronounced and the beta-blockade after 24 hours more effective.

The assessment of risks, benefits and availability of non-narcotic analgesics. A commonsense approach.

In Indonesia, about 50% of all available non-narcotic analgesics are marketed as single drugs and the other half comprise fixed combination products. Each country should decide through a national drug policy which drugs are to be available, but it is important such policies be flexible and cognisant of the needs of the public and of the pharmaceutical industry. A drug should not be withdrawn from the market without an objective scientific assessment of its benefit-risk ratio. However, reevaluation of some drugs marketed previously should be undertaken, including combinations of non-narcotic analgesics. Although it is often said that evaluation of drugs should be left to experts in the established drug control agencies and that the third world countries should follow their decisions, there is a good argument for the developing countries to formulate and implement their own drug policies. In evaluating a non-narcotic analgesic, efficacy and safety must be carefully considered and a drug with marginal efficacy should not be approved for use. However, a non-narcotic analgesic with superior efficacy should probably be approved for use even if there is some risk associated with usual therapeutic dosages. Commonsense reasoning demands that drugs should be for the layperson to treat common ailments, although such drugs must fulfil exacting criteria of efficacy, safety and simplicity of use.

A multinational comparison of drug treatment in patients with cerebrovascular disease.

We have compared the frequency with which various drugs were used in patients with cerebrovascular disease in five countries (UK, Italy, Indonesia, Spain and Yugoslavia). There were very large variations in the use of anti-oedema agents, 'cerebral vasodilators', and vitamins, which were not explained by differences in the populations studied. This variation has probably less to do with any scientific validation for the various treatments, which in most cases does not exist, than with medical 'fashion' and commercial pressures. Large variations in prescribing habits for what is thought to be the same disease are undesirable, and reflect a dearth of facts and adequate clinical trials.

An Asian perspective on drug and related health care information.

To ensure that drugs are available in adequate quantity and quality for the health needs of the population and properly used, Asian governments in the past decades have exercised their sovereign rights quite independently and differently. A high number of patients per prescribing physician has consequences for drug information, in regard to both prescribers and consumers needing to self-medicate. To reliably inform patients through physicians, pharmacists, or medical auxiliary personnel is of great importance in the face of an illiteracy problem. Self- medication and illiteracy place emphasis on communication by word of mouth or by pictures. Word of mouth is the most important route, because even with a steady increase in literacy, the increase in transistor radios has been even more pronounced. For specific health information, instructional posters, with emphasis on pictures, have been very effective. Billboards do not allow adequate information disclosure needed for drugs. The opportunity to expand the coverage of consumer drug information, in that labelling for consumers gives additional relevant general health information, seems appropriate.