Indres Moodley

Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung

The effects of selective phosphodiesterase isozyme inhibitors on eosinophil infiltration induced by antigen challenge or by exposure to an aerosol of platelet-activating factor (PAF) were investigated in the guinea-pig. Pretreatment 24 h and 3 h before antigen challenge or PAF exposure with theophylline (100 mg/kg), rolipram (5 mg/kg) and Ro 20-1724 (30 mg/kg) significantly reduced the increase in eosinophil numbers in bronchoalveolar lavage fluid. In contrast, milrinone, SK&F 94-120 and zaprinast were ineffective against antigen-induced eosinophil recruitment. Theophylline, rolipram and Ro 20-1724 also significantly reduced the release of eosinophil peroxidase into the bronchoalveolar lavage fluid. It is suggested that inhibitors of type IV phosphodiesterase have anti-inflammatory effects in the airways and may be useful in the treatment of asthma.

High uptake of Gardasil vaccine among 9 - 12-year-old schoolgirls participating in an HPV vaccination demonstration project in KwaZulu-Natal, South Africa.

BACKGROUND Cervical cancer is linked to infection of the cervix by oncogenic human papillomavirus (HPV) subtypes. The quadrivalent Gardasil vaccine (against HPV types 6, 11, 16, 18), recommended in girls 9 - 12 years of age, has been shown to be safe, immunogenic and efficacious, with minimal or no side-effects. AIM To demonstrate the capacity of school health teams to carry out vaccinations within a school environment. OBJECTIVES To assess the uptake of 3 doses of the vaccine, document lessons learnt and provide recommendations for a national rollout of school-based HPV vaccination for learners. METHODS Female learners (age 9 - 12 years) from 31 primary schools in Nongoma and Ceza districts (KwaZulu-Natal province, South Africa) were identified for inclusion in the vaccination programme. The 3 doses of vaccine were administered by existing school health teams. Education and training sessions were held with all stakeholders: provincial departments of health and education; school health teams; primary healthcare nurses; hospital doctors and nurses; private practitioners; school principals, teachers and governing bodies; parents; and community and traditional leaders. RESULTS The overall uptake of the vaccine was found to be high: 99.7%, 97.9% and 97.8% for the first, second and third doses respectively (N = 963). No adverse events were attributed to the HPV vaccine. CONCLUSION This project demonstrated the successful implementation of HPV vaccination among learners (ages 9 - 12 years) using school health teams.

Plasma histamine in asthmatic and control subjects following exercise: influence of circulating basophils and different assay techniques.

Arterial plasma histamine concentrations were measured after exercise in 10 subjects with extrinsic atopic asthma, 10 who were non-atopic and non-asthmatic and seven who were atopic but non-asthmatic, by a single isotope radioenzymatic assay. Significantly higher plasma histamine concentrations were found in the asthmatic subjects before exercise than in the non-atopic controls (p less than 0.05). The mean histamine concentration rose after exercise in all groups but the increased levels were not significantly different from pre-exercise values. Similarly, mean circulating basophil counts increased in all groups after exercise, and a highly significant correlation was found between basophil counts and whole blood histamine concentrations (p less than 0.001). In vitro studies showed that there was a significant correlation between the number of basophils added to plasma samples and the concentrations of histamine subsequently detected. Although the mean concentrations of plasma histamine and whole blood histamine and number of basophils in the atopic control group were intermediate between those found in the atopic asthmatic and non-atopic controls, none of the differences was significant. Venous plasma histamine concentrations after exercise were measured in a further five subjects with extrinsic atopic asthma and five non-atopic, non-asthmatic subjects before and after exercise with the more sensitive and specific double isotope radioenzymatic assay. Concentrations of plasma histamine measured by this assay were about one tenth of those measured by the single isotope radioenzymatic assay. Although a small rise in mean plasma histamine concentration occurred in both groups after exercise there was no significant difference in these levels either between or within the groups. We find no evidence from these studies on measurement of peripheral blood histamine to support the hypothesis that mast cell mediator release is implicated in the pathogenesis of exercise induced asthma.

Staphylococcus aureus bacteraemia at two academic hospitals in Johannesburg

OBJECTIVES AND METHODS Staphylococcus aureus bacteraemia (SAB) remains a major problem worldwide. A retrospective study of patients with SAB seen from November 1999 to October 2002 was conducted at two academic hospitals in Johannesburg to determine mortality rates (death within 14 days of submission of blood culture) in patients bacteraemic with methicillin-sensitive (MSSA) and resistant S. aureus (MRSA) and to identify risk factors associated with mortality. RESULTS Of 449 patients with SAB, 104 (23.2%) died within 14 days of clinically suspected SAB. Of the 204 patients who acquired SAB in hospital, 6 patients died within 2 days, 39 between 2 and 14 days, and 41 more than 14 days after onset of SAB. One hundred and five patients (23.4%) had MRSA bacteraemia, 21 (20%) originating from the community. The MRSA bacteraemia rate among patients with hospital-acquired infection was 41.1%, significantly higher (p < 0.0001) than the 10.3% community-acquired MRSA bacteraemia. Thirty-five (33.3%) of the 105 patients with MRSA bacteraemia died within 14 days, compared with 69 (20.1%) of 344 MSSA patients (p = 0.0048). Admission to the intensive care unit (ICU) was significantly associated with mortality (p < 0.001)--30 of 79 patients admitted to ICU died (38%). Among 222 patients whose HIV status was known, 117 (52.7%) were positive, and of these 32 died (27.4%), a rate not significantly higher than that among HIV-seronegative patients (18 of 105 patients, p = 0.69). CONCLUSIONS Compared with MSSA, MRSA was shown to be significantly associated with mortality. Stay in ICU and infection with strains resistant to oxacillin, ofloxacin and rifampicin were highly significant predictors for mortality.

Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid Paracetamol Tablets in Fed and Fasted Volunteers

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

Histamine, neutrophil chemotactic factor and circulating basophil levels following exercise in asthmatic and control subjects.

Significant increase in the maximum post‐exercise values of plasma histamine (PH), whole blood histamine (WBH) and neutrophil chemotactic factor (NCF) occurred in arterial blood within the first hour after exercise in asthmatic patients. However, similar changes in PH and WBH also occurred in the control group. Significant increases in circulating basophil counts following exercise were found in both groups, which closely mirrored the changes in PH and NCF, and there was a highly significant correlation between rises in WBH and basophil counts (P < 0.001). When plasma histamine was assayed in venous blood using a more sensitive and specific double isotope radio enzymatic assay no significant alteration in plasma histamine levels was detected in either the asthmatic or the control group. We conclude that there is no evidence from these studies to support the suggestion that mast cell mediator release is involved in the pathogenesis of exercise‐induced asthma, and that any observed changes in levels of PH and NCF after exercise may be related to changes in levels of circulating basophils.

IgG receptors on the mast cell

Antisera to the IgG subclasses, 1, 2a, 2b, and 2c, induced histamine release from mast cells obtained from the peritoneal washings of Lister hooded rats. The maximum responses obtained with anti-IgG1 and anti-IgG2a were as great as that for anti-IgE (more than 60% histamine release). Cells from unresponsive Wistar rats which did not secrete appreciable amounts of histamine in response to any of the antisera, produced on active sensitization with ovalbumin a small but significant response on challenge with anti-IgG1 and anti-IgG2b as well as with anti-IgE. Passive sensitization with rat myeloma serum of mast cells from the unresponsive rats produced a large response on challenge with anti-IgE but no release to the anti-IgG group 2 subclasses. IgE myeloma serum (1∶1000) neutralized the histamine-releasing activity of anti-IgE serum (87% inhibition) and the antisera to all subclasses of IgG. When the IgE in the myeloma serum was inactivated by heating, the response to the IgG antisera remained completely inhibited except for anti-IgG2a where some reversal was observed. When purified myeloma IgE (30 μg/ml) was used in place of whole serum, marked inhibition (86%) of the response to anti-IgE was obtained leaving the responses to the IgE subclasses unaffected (except for IgG2a, which was 65% inhibited).

Synthesis and structure–activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: novel PDE4 inhibitors

A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v.

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6ooo (PEG 6ooo), and hydroxyethylcellulose (HEC) as possible alternatives to the use of HPMC to control the release of cageine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most eflective for the release of caffeiinefrom the core-in-cup compressed tablets, and that PEG 6cux) was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.

Zero-Order Release of Theophylline from a Core-in-Cup Tablet in Sequenced Simulated Gastric and Intestinal Fluid

Core-in-cup tablets containing theophylline were evaluated for their dissolution characteristics in sequenced simulated gastric fluid (SGF) followed by simulated intestinalfluid (SIF). Core-in-cup tablets containing 10% w/w, 20% w/w, and 30% w/w acacia as binder were evaluated for their effects on the time course of release of theophylline. This was done to optimize a formula that could release theophylline at a zero-order rate of release for 8-16 hr in simulated gastrointestinal fluids. Theophylline was released and dissolved from the core-in-cup tablets at a rate that is more consistent with a zero-order dissolution rate than a first-order dissolution rate in both SIG and SIF. The dissolution rates of theophylline from the 10%, 20%, and 30% acacia core-in-cup tablets were 0.87 mg/min, 0.53 mg/min, and 0.27 mg/min, respectively in SGF, and 0.61 mg/min, 0.30 mg/min, and 0.20 mg/min, respectively in SIF. The results indicate that a concentration of 32% w/w acacia in the core tablet will release theophylline at a rate of 0.14 mg/min in SGF for 2 hr followed by SIF for 10 hr.