Distribution modelling of Aedes aegypti in three dengue-endemic areas in Sumatera, Indonesia.

Ae. aegypti is a dengue virus vector and a public health threat in Indonesia. Furthermore, the Dengue Haemoragic Fever (DHF) has spread to all cities in the country, including Bandar Lampung. A species distribution model, Maximum Entropy (MaxEnt), was used to predict the geographic distribution of this vector in three dengue-endemic areas, namely Sukarame, Kemiling, and Tanjung Seneng. Previously, surveillance was conducted to determine the presence of Ae. aegypti. Therefore, this study suggested that environmental variables such as rainfall, temperature, land cover, and population density have influenced the widespread of Ae. aegypti and facilitate its proliferation in the study areas. The influence of the environmental variables was analyzed using a response curve. The model performance was measured by percent contribution, the importance of permutations, and the jackknife test. This study's evaluation indicates that the certainty models for the presence of Ae. aegypti in Sukarame, Kemiling, and Tanjung Seneng were developed extremely well, with respective values of 0.989, 0.993, and 0.969. The results showed that Ae. aegypti is widespread in the three endemic areas. The high population density and land conversion into settlements are influential environmental variables essential in determining the distribution of the vector in three areas of Bandar Lampung. Climatic factors such as rainfall and temperature are supporting aspects in maintaining the habitat of Ae. aegypti in the area. Mapping areas at risk of this dengue vector can aid in planning disease management strategies and identifying priority locations for entomological surveys to control epidemics.

Distribution modelling of Aedes aegypti in three dengue-endemic areas in Sumatera, Indonesia

@#Ae. aegypti is a dengue virus vector and a public health threat in Indonesia. Furthermore, the Dengue Haemoragic Fever (DHF) has spread to all cities in the country, including Bandar Lampung. A species distribution model, Maximum Entropy (MaxEnt), was used to predict the geographic distribution of this vector in three dengue-endemic areas, namely Sukarame, Kemiling, and Tanjung Seneng. Previously, surveillance was conducted to determine the presence of Ae. aegypti. Therefore, this study suggested that environmental variables such as rainfall, temperature, land cover, and population density have influenced the widespread of Ae. aegypti and facilitate its proliferation in the study areas. The influence of the environmental variables was analyzed using a response curve. The model performance was measured by percent contribution, the importance of permutations, and the jackknife test. This study’s evaluation indicates that the certainty models for the presence of Ae. aegypti in Sukarame, Kemiling, and Tanjung Seneng were developed extremely well, with respective values of 0.989, 0.993, and 0.969. The results showed that Ae. aegypti is widespread in the three endemic areas. The high population density and land conversion into settlements are influential environmental variables essential in determining the distribution of the vector in three areas of Bandar Lampung. Climatic factors such as rainfall and temperature are supporting aspects in maintaining the habitat of Ae. aegypti in the area. Mapping areas at risk of this dengue vector can aid in planning disease management strategies and identifying priority locations for entomological surveys to control epidemics.

Publisher Correction: A thirteen-million-year divergence between two lineages of Indonesian coelacanths.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A thirteen-million-year divergence between two lineages of Indonesian coelacanths.

Coelacanth fishes of the genus Latimeria are the only surviving representatives of a basal lineage of vertebrates that originated more than 400 million years ago. Yet, much remains to be unveiled about the diversity and evolutionary history of these 'living fossils' using new molecular data, including the possibility of 'cryptic' species or unknown lineages. Here, we report the discovery of a new specimen in eastern Indonesia allegedly belonging to the species L. menadoensis. Although this specimen was found about 750 km from the known geographical distribution of the species, we found that the molecular divergence between this specimen and others of L. menadoensis was great: 1.8% compared to 0.04% among individuals of L. chalumnae, the other living species of coelacanth. Molecular dating analyses suggested a divergence date of ca. 13 million years ago between the two populations of Indonesian coelacanths. We elaborate a biogeographical scenario to explain the observed genetic divergence of Indonesian coelacanth populations based on oceanic currents and the tectonic history of the region over Miocene to recent. We hypothesize that several populations of coelacanths are likely to live further east of the present capture location, with potentially a new species that remains to be described. Based on this, we call for an international effort to take appropriate measures to protect these fascinating but vulnerable vertebrates which represent among the longest branches on the Tree of Life.

Should medical students learn to develop a personal formulary? An international, multicentre, randomised controlled study.

OBJECTIVE: This study was performed to determine whether students who are trained in developing a personal formulary become more competent in rational prescribing than students who have only learned to use existing formularies. METHODS: This was a multicentre, randomised, controlled study conducted in eight universities in India, Indonesia, the Netherlands, the Russian Federation, Slovakia, South Africa, Spain and Yemen. Five hundred and eighty-three medical students were randomised into three groups: the personal formulary group (PF; 94), the existing formulary group (EF; 98) and the control group (C; 191). The PF group was taught how to develop and use a personal formulary, whereas e the EF group was taught how to review and use an existing formulary. The C group received no additional training and participated only in the tests. Student's prescribing skills were measured by scoring their treatment plans for written patient cases. RESULTS: The mean PF group score increased by 23% compared with 19% for the EF group (p < 0.05) and 6% for controls (p < 0.05). The positive effect of PF training was only significant in universities that had a mainly classic curriculum. CONCLUSION: Training in development and use of a personal formulary was particularly effective in universities with a classic curriculum and with traditional pharmacology teaching. In universities with a general problem-based curriculum, pharmacotherapy teaching can be based on either existing or personal formularies.

Effects of yeast culture and galacto-oligosaccharides on ruminal fermentation in holstein cows.

Four nonlactating, ruminally cannulated Holstein cows were used in a 4 x 4 Latin square design, balanced for residual effects, to evaluate the effects of supplementing dairy cow diets with yeast culture (Trichosporon sericeum; YC), galacto-oligosaccharides (GOS), or the mixture of YC and GOS on ruminal fermentation, microbial N supply, in situ degradation, and energy and nitrogen metabolism. Treatments were arranged in a 2 x 2 factorial as follows: 1) basal diet, 2) basal diet plus 10 g/d YC, 3) basal diet plus 2% GOS, 4) basal diet plus a mixture of 10 g/d YC and 2% GOS. Nitrogen losses in urine were lower, and retained N was higher, for cows supplemented with a mixture of YC and GOS. Ruminal pH was lower in cows supplemented with GOS alone compared with other treatments. Total VFA concentration was higher in cows fed control and GOS-supplemented diets than in those fed YC containing diets. The molar proportion of propionate was higher, and the molar proportion of acetate was lower, in cows fed control diets. Microbial N supply was higher in cows fed control diets. There were no major positive effects of supplements observed in this study. However, supplementation of a mixture of YC and GOS had a tendency for synergistic effects on N metabolism and in situ degradation of a soluble fraction of oat straw DM and CP of concentrates compared with supplementation of YC or GOS alone.

Effect of Escherichia coli wild type or its derivative with high nitrite reductase activity on in vitro ruminal methanogenesis and nitrate/nitrite reduction.

The effects of two kinds of Escherichia coli strains, wild-type E. coli W3110 or E. coli nir-Ptac, which has enhanced nitrite reduction activity, on in vitro CH4 production and nitrate and nitrite reduction in cultures of mixed ruminal microorganisms was investigated using continuous incubation systems. Escherichia coli nir-Ptac, a derivative of wild-type E. coli W3110, was constructed by replacing self promoter of nir BD operon encoding subunits of nitrite reductase in E. coli W3110 by tac promoter to make the expression of nir BD higher and constitutive. The nitrite reductase activity of E. coli nir-Ptac was approximately twice as high as E. coli W3110. The culture media consisted of 400 mL of strained ruminal fluid taken from two nonlactating Holstein cows receiving a basal diet of orchardgrass hay at maintenance level (55 g of DM/kg of BW0.75 daily), and 400 mL of autoclaved artificial saliva. Treatments were arranged in two separate 3 x 3 factorials consisting of nitrate (NaNO3; 0, 5, or 10 mM) without E. coli or inoculated with E. coli W3110 or E. coli nir-Ptac, or nitrite (NaNO2; 0, 1 or 2 mM) without E. coli or inoculated with E. coli W3110 or E. coli nir-Ptac. The control culture contained no chemical or microbial additives. Escherichia coli cells were inoculated into in vitro mixed ruminal cultures at approximately 2 x 10(8) to 10(9) cells/mL. Methane production by ruminal microorganisms was decreased markedly (P < 0.001) by the addition of nitrate and nitrite, and by the inoculation of cultures with E. coli W3110 or E. coli nir-Ptac (P < 0.01). With mixed nitrite-containing cultures, E. coli nir-Ptac inhibited (P < 0.001) in vitro nitrite accumulation and CH4 production more than E. coli W3110, which may be due to the tac promoter-enhanced nitrite reductase activity of E. coli nir-Ptac accelerating electrons to be consumed for nitrite reduction rather than CH4 biosynthesis. In conclusion, anaerobic cultures of E. coli W3110 or E. coli nir-Ptac may decrease CH4 production in the rumen. The inoculation of E. coli W3110 or, especially, E. coli nir-Ptac to mixed ruminal microorganisms may decrease nitrite toxicity when ruminants consume high-nitrate-containing forages and when nitrite is applied to abate ruminal CH4 production.

Chromatin-dependent cooperativity between constitutive and inducible activation domains in CREB.

The cyclic AMP (cAMP)-responsive factor CREB induces target gene expression via constitutive (Q2) and inducible (KID, for kinase-inducible domain) activation domains that function synergistically in response to cellular signals. KID stimulates transcription via a phospho (Ser133)-dependent interaction with the coactivator paralogs CREB binding protein and p300, whereas Q2 recruits the TFIID complex via a direct association with hTAF(II)130. Here we investigate the mechanism underlying cooperativity between the Q2 domain and KID in CREB by in vitro transcription assay with naked DNA and chromatin templates containing the cAMP-responsive somatostatin promoter. The Q2 domain was highly active on a naked DNA template, and Ser133 phosphorylation had no additional effect on transcriptional initiation in crude extracts. Q2 activity was repressed on a chromatin template, however, and this repression was relieved by the phospho (Ser133) KID-dependent recruitment of p300 histone acetyltransferase activity to the promoter. In chromatin immunoprecipitation assays of NIH 3T3 cells, cAMP-dependent recruitment of p300 to the somatostatin promoter stimulated acetylation of histone H4. Correspondingly, overexpression of hTAFII130 potentiated CREB activity in cells exposed to cAMP, but had no effect on reporter gene expression in unstimulated cells. We propose that cooperativity between the KID and Q2 domains proceeds via a chromatin-dependent mechanism in which recruitment of p300 facilitates subsequent interaction of CREB with TFIID.

Function and factor interactions of a locus control region element in the mouse T cell receptor-alpha/Dad1 gene locus.

Locus control regions (LCRs) refer to cis-acting elements composed of several DNase I hypersensitive sites, which synergize to protect transgenes from integration-site dependent effects in a tissue-specific manner. LCRs have been identified in many immunologically important gene loci, including one between the TCRdelta/TCRalpha gene segments and the ubiquitously expressed Dad1 gene. Expression of a transgene under the control of all the LCR elements is T cell specific. However, a subfragment of this LCR is functional in a wide variety of tissues. How a ubiquitously active element can participate in tissue-restricted LCR activity is not clear. In this study, we localize the ubiquitously active sequences of the TCR-alpha LCR to an 800-bp region containing a prominent DNase hypersensitive site. In isolation, the activity in this region suppresses position effect transgene silencing in many tissues. A combination of in vivo footprint examination of this element in widely active transgene and EMSAs revealed tissue-unrestricted factor occupancy patterns and binding of several ubiquitously expressed transcription factors. In contrast, tissue-specific, differential protein occupancies at this element were observed in the endogenous locus or full-length LCR transgene. We identified tissue-restricted AML-1 and Elf-1 as proteins that potentially act via this element. These data demonstrate that a widely active LCR module can synergize with other LCR components to produce tissue-specific LCR activity through differential protein occupancy and function and provide evidence to support a role for this LCR module in the regulation of both TCR and Dad1 genes.

Control of organ-specific demethylation by an element of the T-cell receptor-alpha locus control region.

DNA methylation is important for mammalian development and the control of gene expression. Recent data suggest that DNA methylation causes chromatin closure and gene silencing. During development, tissue specifically expressed gene loci become selectively demethylated in the appropriate cell types by poorly understood processes. Locus control regions (LCRs), which are cis-acting elements providing stable, tissue-specific expression to linked transgenes in chromatin, may play a role in tissue-specific DNA demethylation. We studied the methylation status of the LCR for the mouse T-cell receptor alpha/delta locus using a novel assay for scanning large distances of DNA for methylation sites. Tissue-specific functions of this LCR depend largely on two DNase I-hypersensitive site clusters (HS), HS1 (T-cell receptor alpha enhancer) and HS1'. We report that these HS induce lymphoid organ-specific DNA demethylation in a region located 3.8 kilobases away with little effect on intervening, methylated DNA. This demethylation is impaired in mice with a germline deletion of the HS1/HS1' clusters. Using 5'-deletion mutants of a transgenic LCR reporter gene construct, we show that HS1' can act in the absence of HS1 to direct this tissue-specific DNA demethylation event. Thus, elements of an LCR can control tissue-specific DNA methylation patterns both in transgenes and inside its native locus.

Geriatric prescribing in the medical wards of a teaching hospital in Nepal.

A retrospective study on prescribing patterns for 100 randomly selected geriatric patients admitted over a period of 1 year to the medical wards of the Tribhuvan University Teaching Hospital (TUTH) in Nepal showed that polypharmacy was prevalent. During a hospital stay, 73% patients received more than five, 54% received more than eight, and 24% received more than nine drugs concurrently. Although the average drug exposure per patient during a hospital stay was found to be 11.2, this figure would actually go up to 14.5 if all the active ingredients of the fixed-dose combination products prescribed (15.4% of all drugs) were taken into account. Intravenous fluids were the most commonly prescribed drugs and were given to 91% of the patients. Antibiotics (excluding metronidazole and antituberculous drugs) were given to over three-quarters (77%) of the patients. Ciprofloxacin was the most commonly prescribed antibiotic. Of the 42 patients treated with this drug, 31 (73.8%) received it intravenously, either for a part of or throughout the course. This antibiotic was prescribed concurrently with theophylline in 14 patients without the facility for monitoring plasma-theophylline levels. It was also administered at the same time as antacid in nine patients. Nearly half (46.4%) of the drugs were prescribed by brand or proprietary names. The prescribing error of leaving the prescription card undated or unsigned when prescribing or stopping drugs was found to be high. The results of this survey indicate that there is considerable scope for improving geriatric prescribing practices in the medical wards of TUTH.

Small group intervention vs formal seminar for improving appropriate drug use.

In an attempt to evaluate the efficacy of different methods of interventions to improve the appropriate use of drugs for acute diarrhoea, a controlled study has been carried out in 6 districts in Yogyakarta and Central Java provinces, Indonesia. This study was designed to investigate the impacts of two different methods of educational intervention, i.e. a small group face-to-face intervention and a formal seminar for prescribers, on prescribing practice in acute diarrhoea. The districts were randomly assigned into 3 groups and 15 health centers were selected from each district. Prescribers in Group 1 underwent a small group face-to-face intervention conducted in the respective health center. Those in Group 2 attended a formal seminar conducted at the district level. Prescribers in Group 3 served as the control group. Both interventions were given on a single occasion without follow-up supervision or monitoring. Written information materials on the appropriate management of acute diarrhoea were developed and were provided to all prescribers in the intervention groups. Focus group discussions (FGDs) involving prescribers and consumers in the 6 districts were carried out to identify various underlying motivations of drug use in acute diarrhoea. The findings of the FGDs were used as part of the intervention materials. To evaluate the impacts of these interventions on prescribing practice, a prescribing survey for patients under five years old with acute diarrhoea was carried out in health centers covering 3-month periods before and after the intervention. The results showed that both interventions were equally effective in improving the levels of knowledge of prescribers about the appropriate management of acute diarrhoea. They were also partially effective in improving the appropriate use of drugs, reducing the use of non-rehydration medications. There was a highly significant reduction of antimicrobial usage either after small-group face-to-face intervention (77.4 +/- 2.7% to 60.4 +/- 2.9%; P < 0.001) or formal seminar (82.3 +/- 3.0% to 72.3 +/- 3.6%; P < 0.001), and the former caused significantly (P < 0.001) greater reduction than the latter. There was also a significant (P < 0.01) reduction in the usage of antidiarrhoeals after both interventions, i.e. from 20.3 +/- 3.7% to 12.5 +/- 3.3% (P < 0.01) after face-to-face intervention and from 48.5 +/- 4.1% to 27.0 +/- 4.3% (P < 0.01) after seminar. However, the formal seminar had a significantly (P < 0.01) greater impact than the small group face-to-face intervention. There was also a trend toward increased oral rehydration solution (ORS) usage after both interventions, but this did not achieve the level of statistical significance (P > 0.05). No changes were observed in the control group. Although the small group face-to-face intervention did not appear to offer greater impacts over large seminars in improving the appropriate use of drugs in acute diarrhoea, since the unit cost of training is far less costly than the seminar, it might be feasibly implemented in the existing supervisory structure of the health system.

Interactional group discussion: results of a controlled trial using a behavioral intervention to reduce the use of injections in public health facilities.

Injections are commonly overused in Indonesia. More than 60% of patients attending public health facilities receive at least one injection, which increases clinical risk and has adverse economic impact. This study assesses the efficacy of an innovative behavioral intervention, the Interactional Group Discussion (IGD), for reducing the overuse of injections. This study was a controlled trial in a single district with 24 public health centers randomized to intervention and control groups. Prescribers in the intervention group were invited to one IGD, each of which consisted of 6 prescribers and 6 patients; a total of 24 IGDs were held in a 4-week period, and all invited prescribers participated. The groups, which lasted 90-120 minutes, were facilitated by a behavioral scientist and a clinician, who also served as a scientific resource person. The hypothesized mechanism of behavior change involved reality testing prescribers' assumptions about patient beliefs, imparting scientific information about injection efficacy, and establishing peer norms about correct behavior. Outcomes were measured by a retrospective prescribing survey covering the periods 3 months before and 3 months after the intervention, with samples of 100 prescriptions per center per month. Rates of injection and average number of drugs per prescription were computed separately for each center, and t-tests were used to compare pre-post changes in outcomes in both groups. Results showed a significant decrease in injection use from 69.5 to 42.3% in the intervention group, compared to a decrease from 75.6 to 67.1% among controls [-18.7.0% intervention vs control, 95% CI = (-31.1%, -6.4%), P < 0.025]. There was also a significant reduction in average number of drugs per prescription [-0.37 drugs prescribed per patient, 95% CI = (-0.04, -0.52), P < 0.05], indicating that injections were not substituted with other drugs. We conclude that the IGD significantly reduces the overuse of injections. It is suggested to try out other behavioral interventions to improve the rational use of drugs.

Impact of a short course in pharmacotherapy for undergraduate medical students: an international randomised controlled study.

Irrational prescribing is a habit which is difficult to cure. However, prevention is possible and for this reason the WHO Action Programme on Essential Drugs aims to improve the teaching of pharmacotherapy to medical students. The impact of a short problem-based training course in pharmacotherapy, using a WHO manual on the principles of rational prescribing, was measured in an international multi-centre randomised controlled study of 219 undergraduate medical students in Groningen (Netherlands), Kathmandu (Nepal), Lagos (Nigeria), Newcastle (Australia), New Delhi (India), San Francisco (USA), and Yogyakarta (Japan). The manual and the course presented the students, who were about to enter the clinical phase of their studies, with a normative model for pharmacotherapeutic reasoning in which they were taught to generate a "standard" pharmacotherapeutic approach to common disorders, resulting in a set of first-choice drugs called P(ersonal)-drugs. The students were then taught how to apply this set of P-drugs to specific patient problems on the symptomatic treatment of pain, using a six-step problem-solving routine. The impact of the course was measured by tests before training, immediately after, and six months later. After the course, students from the study group performed significantly better than controls in all patient problems presented (p < 0.05). The students not only remembered how to solve old problems, but they could also apply their skills to new problems. Both retention and transfer effect were maintained at least six months after the training session in all seven medical schools. In view of the impossibility of teaching students all basic knowledge on the thousands of drugs available, this approach seems to be an efficient way of teaching rational prescribing. However, the method should be accompanied by a change in teaching methods away from the habit of transferring knowledge about the drugs towards problem-based teaching of therapeutic reasoning.

Field tests for rational drug use in twelve developing countries.

Increasing efforts are being made to improve drug-use practices and prescribing behaviour in developing countries. An essential tool for such work is an objective and standard method of assessment. We present here a set of drug-use indicators produced and tested in twelve developing countries. We describe practical applications, which include the use of indicators to increase awareness among prescribers in Malawi and Bangladesh, to identify priorities for action (eg, polypharmacy in Indonesia and Nigeria, overuse of injections in Uganda, Sudan, and Nigeria, and low percentage of patients who understood the dosage schedule in Malawi), and to quantify the impact of interventions in Yemen, Uganda, Sudan, and Zimbabwe.

PIP: A set of drug-use indicators produced and tested in 12 developing countries and the recommended method for data collection are presented to improve drug use and prescribing behavior. The International Network for the Rational Use of Drugs in collaboration with the WHO Action Program on Essential Drugs undertook a project to develop and field-test a set of basic drug-use indicators. The method for collecting the data was first tested in Indonesia, Bangladesh, and Nepal; other tests took place in Guatemala, Malawi, Nigeria, Tanzania, and well as in Ecuador, Sudan, and Zimbabwe. In results from 12 developing countries, drug-use patterns were ascertained. The average numbers of drugs per encounter were high in Indonesia and Nigeria (3.3 and 3.8); the prescriptions of 1 or more antibiotics were also high in Uganda and Sudan (56% and 63%), similar to injectable drugs in Uganda, Sudan, and Nigeria (36-48%); and the availability of essential drugs was low in Ecuador (38%). 94% of drugs were prescribed by generic name in Zimbabwe, whereas only 37% were in Ecuador. In Yemen the comparison of an essential drugs project area to a control area demonstrated 1.5 and 2.4 drugs per encounter, 46% and 67% of them antibiotics and 22% and 45% of them injections, respectively. In Uganda, a study on the effect of training showed decline in the use of injections (50% to 41%), improvement in the use of oral rehydration treatment for diarrhea (52% to 89%), and reduction in antidiarrheal drug use (60% to 39%). In rural health facilities in Sudan the drugs prescribed by generic name increased from 17% to 70% between 1989 and 1991. In 10 developing countries the average number of drugs per prescription for general outpatient encounters ranges from 1.3 to 2.2., but in Indonesia and Nigeria it is 3.3 and 3.8. The median of 41% of antibiotics prescribed in the 12 countries reflects actual prescribing, not optimum values.

A strategy for promoting improved pharmaceutical use: the International Network for Rational Use of Drugs.

Over the last decade, pharmaceutical selection, procurement, distribution, and financing have improved as a result of essential drugs programs. However, despite improved availability, pharmaceuticals are frequently used irrationally. The International Network for the Rational Use of Drugs (INRUD) has been established to help address this problem. The Network joins core groups of researchers from four African and three Asian countries with support groups in Boston, Sweden, WHO, and Australia. The activities of the Network are supported by multilateral, bilateral, foundation donors and by Management Sciences for Health. INRUD functions as a participatory organization in which members are involved in decision-making. The primary objective of the Network is to identify through a coordinated set of country-based research projects a set of effective interventions to recommend as policy options for the promotion of rational drug use. In developing these research projects, INRUD stresses the importance of a multi-disciplinary perspective for adequately understanding the reasons underlying inappropriate use of drugs. To better enable country groups to utilize strong research methodologies and to blend the strengths of multiple disciplines effectively, a major activity of the Network thus far has been the building of local research capacity.

Pharmacokinetics of metronidazole in saliva.

Measurement of metronidazole concentration and its pharmacokinetics from saliva and serum samples have been conducted in 8 healthy volunteers. The pharmacokinetic study was carried out after an oral ingestion of 500 mg tablet of the drug, simultaneously from saliva and serum samples. The study showed a significant positive correlation between saliva and serum metronidazole concentrations. However, a better correlation was obtained during the elimination phase (r = 0.90, n = 51, p less than 0.001) compared to that during the absorption phase (r = 0.76, n = 26, p less than 0.001). The overall ratio of saliva to serum concentration was 0.93 +/- (SEM 0.05). Not surprisingly, the half-life of metronidazole obtained from saliva samples (8.03 +/- SEM 0.59 hours) was similar to that from serum (7.97 +/- SEM 0.39 hours). The mean area under the drug concentration (AUC0-infinity) in saliva was 153.56 +/- (SEM 16.42 micrograms/ml hour) and that in serum was 179.76 +/- (SEM 11.70 micrograms/ml hour), yielding a saliva to serum ratio of 0.87 (+/- SEM 0.10). It could be concluded, therefore, that the measurement of metronidazole concentration from saliva can be used for the estimation of its pharmacokinetics and may also be used as reliable and convenient method for bioequivalence studies.

The relative bioavailability of diclofenac with respect to time of administration.

The pharmacokinetics of diclofenac after a single oral dose (50 mg) were studied in 10 healthy adults on two occasions separated by 2 weeks, once in the morning (dose administered at 07.00 h) and once in the evening (dose at 19.00 h). Peak serum drug concentrations as well as the area under the drug concentration-time curve were significantly less during the night compared with the day (Cmax: 1886 +/- s.d 901 vs 2791 +/- 1565 ng ml-1 and AUC: 2807 +/- 1376 vs 3681 +/- 1986 ng ml-1 h). However, the time to reach peak concentration (tmax) and the half-life of diclofenac (t1/2) were not significantly different on the two occasions. We suggest that the extent of diclofenac absorption is slightly lower following administration in the evening compared with administration in the morning.

Lowering of theophylline clearance by isoniazid in slow and rapid acetylators.

The effect of isoniazid (INH) pretreatment (400 mg daily for 2 weeks) on the elimination kinetics of theophylline (given intravenously as aminophylline equivalent to 151.2 mg theophylline) was investigated in 13 healthy male non-smokers. Amongst the 13 subjects studied, seven were rapid and six were slow acetylators. The mean clearance of theophylline was significantly lowered after INH (2.20 +/- 0.24 l h-1) (mean +/- s.e. mean) compared with the baseline value (2.80 +/- 0.24 l h-1). The volume of distribution at steady state was also lowered significantly after INH (0.42 +/- 0.01 l kg-1 vs 0.47 +/- 0.02 l kg-1). Consequently, there was no significant prolongation of theophylline half-life after INH (7.0 +/- 0.3 h vs 6.7 +/- 0.4 h control). The lowering of theophylline clearance by INH may be related to acetylator status since slow acetylators showed a greater interaction than rapid acetylators. However, this difference was not statistically significant.

Esophageal atresia--a rabbit model to study anastomotic healing and the use of tissue adhesive fibrin sealant.

The problem of bringing together two relatively widely separated, small, and fragile ends of a sick newborn baby's atretic esophagus remains a formidable surgical task, wherein the incidence of anastomotic leakage ranges from 10% to 27%. Recently, a multicomponent tissue adhesive fibrin sealant (Tisseel) has been licensed in Canada and declared useful for sealing gastrointestinal (GI) tract anastomoses. To study whether Tisseel might decrease the leakage rate of esophageal anastomoses in neonatal esophageal atresia and perhaps limit stricture formation, a rabbit model of esophageal atresia was developed. Twenty New Zealand white rabbits weighing 2.8 to 3.7 kg underwent thoracotomy and resection of a segment of esophagus with end-to-end, interrupted silk-sutured anastomosis under tension, to mimic the conditions found in newborn esophageal atresia. Four died immediately following operation. Ten rabbits had their anastomosis sealed with Tisseel, six control animals did not. All animals consumed variable amounts of water and food, starting 24 hours after surgery. Survival averaged 10.5 days (range, 5 to 20 days). Eight animals (five experimental, three control) were evaluated by means of barium esophagograms 1 week postoperatively, and all except one control animal demonstrated radiologic evidence of anastomotic leakage. Autopsy specimens revealed gross leakage in nine animals (seven experimental, two control). However, histology revealed leakage and periesophageal abscess formation in all experimental animals and in four control animals. The remaining two controls revealed only some degree of esophageal stenosis. This experiment showed no demonstrable benefit from the use of a fibrin sealant in preventing esophageal anastomotic leakage, such as that which occurs in repaired esophageal atresia.