CXCL1 is a negative regulator of mast cell chemotaxis to airway smooth muscle cell products in vitro.

BACKGROUND: Activated mast cells (MC) numbers on airway smooth muscle (ASM) are increased in eosinophilic asthma. In vitro, asthmatic cytokine-stimulated ASM cell-conditioned medium (CM) induces more MC chemotaxis than CM from nonasthmatic ASM cells. Intriguingly the nonasthmatic ASM CM inhibits MC chemotaxis to the asthmatic ASM CM. However, the inhibitory factor(s) in the nonasthmatic ASM CM is still to be identified. OBJECTIVE: To identify the factor(s) released by nonasthmatic ASM cells that inhibits MC chemotaxis. METHODS: Confluent, serum-starved ASM cells from donors with and without asthma were stimulated with IL-1ß and T-helper (Th)1 (TNFα and IFNγ) or Th2 (IL-4, IL-13) cytokines, or left unstimulated. CM samples were collected after 24 h, and a potential inhibitory factor identified using cytokine protein arrays. Its production was assessed using ELISA and RT-PCR and inhibitory role investigated in MC chemotaxis and Ca(2+) mobilization assays. RESULTS: Only CXCL1 was produced in greater amounts by nonasthmatic than asthmatic ASM cells following Th1 and Th2 cytokine stimulation. CXCL1 mRNA expression was also increased. Exogenous rh-CXCL1 significantly inhibited MC intracellular Ca(2+) mobilization and chemotaxis to either CXCL10, CXCL8 or CM collected from asthmatic ASM cells following Th1 or Th2 cytokine stimulation. Neutralizing CXCL1 in nonasthmatic ASM CM or blocking its receptor significantly promoted MC chemotaxis. CONCLUSIONS: CXCL1 was a major factor regulating MC chemotaxis in vitro. Its differential release by ASM cells may explain the differences observed in MC localization to the ASM of people with and without asthma. CLINICAL RELEVANCE: CXCL1 inhibition of MC recruitment to the ASM may lead to new targets to limit asthma pathophysiology.

Airway smooth muscle CXCR3 ligand production: regulation by JAK-STAT1 and intracellular Ca²âº.

In asthma, airway smooth muscle (ASM) chemokine (C-X-C motif) receptor 3 (CXCR3) ligand production may attract mast cells or T lymphocytes to the ASM, where they can modulate ASM functions. In ASM cells (ASMCs) from people with or without asthma, we aimed to investigate JAK-STAT1, JNK, and Ca²âº involvement in chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11 production stimulated by interferon-γ, IL-1ß, and TNF-α combined (cytomix). Confluent, growth-arrested ASMC were treated with inhibitors for pan-JAK (pyridone-6), JAK2 (AG-490), JNK (SP-600125), or the sarco(endo)plasmic reticulum Ca²âºATPase (SERCA) pump (thapsigargin), Ca²âº chelator (BAPTA-AM), or vehicle before and during cytomix stimulation for up to 24 h. Signaling protein activation as well as CXCL10/CXCL11 mRNA and protein production were examined using immunoblot analysis, real-time PCR, and ELISA, respectively. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to pyridone-6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion. Neither agent caused additional inhibition of release when used in combination with the JNK inhibitor SP-600125. Conversely, p65 NF-κB activation was higher in asthmatic than nonasthmatic ASMCs. BAPTA-AM abolished early CXCL10/CXCL11 mRNA production, whereas thapsigargin reduced it in asthmatic cells and inhibited CXCL10/CXCL11 release by both ASMC types. Despite these inhibitory effects, neither Ca²âº agent affected early activation of STAT1, JNK, or p65 NF-κB. In conclusion, intracellular Ca²âº regulated CXCL10/CXCL11 production but not early activation of the signaling molecules involved. In asthma, reduced ASM STAT1-JNK activation, increased NF-κB activation, and altered Ca²âº handling may contribute to rapid CXCR3 ligand production and enhanced inflammatory cell recruitment.

Human lung mast cells modulate the functions of airway smooth muscle cells in asthma.

BACKGROUND: Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction. OBJECTIVES: To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. METHODS: Freshly isolated human lung mast cells were stimulated with IgE/anti-IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays. RESULTS: Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation. CONCLUSIONS: Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma.

Diabetes management in an Australian primary care population.

WHAT IS KNOWN AND OBJECTIVE: Worldwide studies have shown that significant proportions of patients with type 2 diabetes (T2DM) do not meet targets for glycaemic control, blood pressure (BP) and lipids, putting them at higher risk of developing complications. However, little is known about medicines management in Australian primary care populations with T2DM. The aim of this study was to (i) describe the management of a large group of patients in primary care, (ii) identify areas for improvement in management and (iii) determine any relationship between adherence and glycaemic, BP and lipid control. METHODS: This was a retrospective, epidemiological study of primary care patients with T2DM diabetes, with HbA(1c) of >7%, recruited in 90 Australian community pharmacies. Data collected included demographic details, diabetes history, current medication regimen, height, weight, BP, physical activity and smoking status. RESULTS AND DISCUSSION: Of the 430 patients, 98% used antidiabetics, 80% antihypertensives, 73% lipid lowering drugs and 38% aspirin. BP and all lipid targets were met by only 21% and 14% of the treated patients and 21% and 12% of the untreated patients respectively. Medication adherence was related to better glycaemic control (P = 0.04). WHAT IS NEW AND CONCLUSIONS: An evidence-base prescribing practice gap was seen in this Australian primary care population of T2DM patients. Patients were undertreated with antihypertensive and lipid lowering medication, and several subgroups with co-morbidities were not receiving the recommended pharmacotherapy. Interventions are required to redress the current evidence-base prescribing practice gap in disease management in primary care.

Phosphoramidon potentiates the contractile response to endothelin-3, but not endothelin-1 in isolated airway tissue.

1. Phosphoramidon (10 microM) markedly increased the contractile response to endothelin-3 in human and rabbit bronchus in vitro. In human tissue the contractile response to 0.3 microM endothelin-3 was significantly increased from 54 +/- 12% to 137 +/- 34% (of the response to 1 nM acetylcholine) in the presence of phosphoramidon. Similarly, in rabbit isolated bronchus, the endothelin-3-induced response was increased from 34 +/- 5% to 61 +/- 7%. 2. In addition, the potency (as measured by EC30 values) of this peptide in human and rabbit airways was significantly augmented in the presence of the enzyme inhibitor. The geometric mean EC30 value was decreased from 53 nM (95% CI:15, 190) to 8 nM (95% CI:3, 23) in human bronchus and from 150 nM (95% CI:89, 250) to 23 nM (95% CI:11, 50) in rabbit tissue. 3. Neither the potency nor the response (at 0.3 microM) to endothelin-3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon. 4. A previous study carried out in human airways has implied that the difference in potency between endothelin-1 and endothelin-3 may be attributed to a heterogeneous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this marked difference, as well as that obvious in rabbit airway tissue can be abolished in the presence of phosphoramidon. 5. Phosphoramidon produced no change in the cumulative concentration-response curve for endothelin-1 in airway tissue from the three species studied. 6. These results suggest that a phosphoramidon-sensitive enzyme (probably neutral endopeptidase) found in lung, may be responsible for local degradation of endothelin-3, but not endothelin-l in human and rabbit isolated bronchus.

The mechanism of action of endothelin in human lung.

1 The peptides endothelin-1 (ET-1) and endothelin-2 (ET-2) elicited potent and sustained contractions of human isolated bronchus and pulmonary artery. 2 ET-1 is one of the most potent contractile agonists investigated in these tissues with an EC50 value of 18.3 nM (95% confidence interval: 12.9, 25.9 nM: n = 26) in bronchus and 3.2 nM (95% confidence interval: 0.4, 23.9 nM; n = 5) in the arterial preparation. 3 ET-1 is 2.5 times more potent than ET-2 in both the airway and vascular tissues, and both forms of the peptide have geometric mean EC50 values 5 times greater than in the isolated bronchial tissue than in the pulmonary artery. 4 Neither pretreatment with the voltage-dependent calcium (VDC) channel antagonist verapamil (10 microM) nor with indomethacin (25 microM) significantly altered the response curve to ET-1 in human isolated bronchus. Removal of calcium from the Krebs-Henseleit solution did not affect ET-1-induced responses. 5 Specific binding on the smooth muscle of human airway and pulmonary arterial tissue to both ET-1 and ET-2 was detected in autoradiographic studies. There appeared to be no difference between the peptides in the location nor the density of binding sites. 6 We conclude that contraction of human bronchial tissue by ET-1 is not dependent upon influence of extracellular calcium nor release of prostaglandins or thromboxane A2. It is likely that the action of ET-1 in this tissue is due to binding of this peptide to specific receptors located on the smooth muscle.

Tachykinin receptors in rabbit airways--characterization by functional, autoradiographic and binding studies.

1. In many species, both NK1 and NK2 tachykinin receptors appear to be important in mediating the contraction of airway smooth muscle. We have examined the distribution and characterization of receptors for tachykinins in rabbit airways using functional length tension studies, autoradiography and radioligand binding studies. 2. Contractile responses to tachykinins were elicited in four different areas of the respiratory tree--trachea, and three progressively more distal areas of the right bronchus. The NK2 receptor-preferring agonists, neurokinin A (NKA), neuropeptide gamma (NP gamma) and the NK2-selective [Lys5 MeLeu9, Nle10]-NKA(4-10) [NKA (4-10) analogue] produced similar contraction in all four areas. Substance P (SP) and the NK1-selective [Sar9,Met(O2)11]-SP (Sar-SP) exhibited a marked location-dependence in the magnitude of contraction, producing minimal contraction in the trachea and more proximal bronchi with contractions becoming progressively larger in the more distal airways. Senktide (which is selective for the NK3 receptor) produced negligible contraction in all areas. 3. The NK2-selective antagonist, MDL29,913, was a weak antagonist of NKA and NKA(4-10) analogue. At a concentration of 2 microM, it produced a small but significant shift in the response curve to NKA and a greater shift (8 fold) in the curve to NKA(4-10) analogue, but it had no effect on responses to Sar-SP. The non peptide NK1 receptor antagonist, CP-96,345, was also unexpectedly weak in this preparation. The pD2 value for Sar-SP was decreased 27 fold by CP-96,345 at a concentration of 1 microM, without alteration in the maximum response.4. Autoradiographic binding sites to ['251I]-NKA were sparse over smooth muscle in proximal airway preparations and markedly increased in density in the more distal airways. There was negligible binding over vascular smooth muscle and epithelium.5. Radioligand binding studies revealed binding to ['251I]-NKA which was 82% specific. The order of potency for inhibition of ['251I]-NKA binding was SP> = Sar-SP> NKA = NPy>CP-96,345> NKA(4-10) analogue >NKB>>>MEN 10207 (the NK2 subtype selective antagonist) >MDL 29,913> senktide. This profile indicates binding predominantly to NK, receptors.6. These results suggest that there are at least two types of tachykinin receptors in rabbit airways, a population of NK, receptors, the density of which is greatest in the periphery and, in addition, NK2 receptors which are uniformly distributed throughout the airways. These receptors have unusual characteristics in that the NK, antagonist, CP-96,345 and the NK2 antagonist, MDL 29,913 respectively exhibited only weak potency.

Drug utilisation review (DUR) of the third generation cephalosporins. Focus on ceftriaxone, ceftazidime and cefotaxime.

Six parenteral third generation cephalosporins have been introduced into clinical use in the past 10 years. The 3 most frequently available agents are cefotaxime, ceftriaxone and ceftazidime. These 3 third generation cephalosporins are characterised by a broad spectrum of activity and increased stability to beta-lactamases compared with the first and second generation cephalosporins. However, there are growing numbers of reports of resistance to these agents with increasing use. The major differences in the properties of the 3 agents are the long half-life of ceftriaxone and its dual route of elimination. Ceftazidime is best restricted to Pseudomonas aeruginosa infections where other agents are contraindicated or ineffective. Cefotaxime and ceftriaxone can be used in nosocomial Gram-negative infections where P. aeruginosa can be ruled out. The types and incidences of adverse drug reactions are not different for the 3 agents. A number of drug utilisation review (DUR) studies of these agents in the hospital setting have reported a considerable incidence of inappropriate use and substantial avoidable costs. There are methodological problems with most of the DUR studies, especially the criteria and the methods of cost estimation. The use of pharmacoeconomic methodology could ensure more realistic cost estimation; however, outcome data are, in most cases, not available.

Epidemiology of Haemophilus influenzae type b meningitis in Manila, Philippines, 1994 to 1996.

BACKGROUND: Effective vaccines against Haemophilus influenzae type b (Hib) have shown impressive results in decreasing Hib meningitis in developed countries. In the Philippines Hib vaccines are not part of the routine immunization given to children. Before a decision can be made to include Hib vaccines in immunization program, epidemiology of Hib meningitis in Manila, Philippines, should first be described. METHODOLOGY: A cohort of 41,592 children <5 years of age in Central Manila was the study population. Confirmed cases between January, 1994, and December, 1996, were obtained from all hospitals in the region. Confirmation of cases was based on positive culture isolated from blood or cerebrospinal fluid (CSF) or Hib antigen identified in CSF with a clinical diagnosis of Hib meningitis. The progress of children with Hib meningitis postinfection was evaluated from hospital records. RESULTS: There were 118 episodes of Hib meningitis identified in the population in the study period. Sequelae occurred in 15% of the total cases, and the case fatality rate was 11%. The annual incidence of Hib meningitis in Manila for children <5 years old was 95 per 100,000. CONCLUSIONS: Hib meningitis in Central Manila is common. The incidence is particularly high in children <6 months old. Adverse neurologic outcomes and a high case fatality rate in children younger than 1 year suggest that a vaccination program would be useful.

Substance P-induced contraction of rabbit airways: mechanism of action.

The mechanism by which substance P induces contraction of airway smooth muscle has been the subject of numerous reports. It has been suggested that in rabbit airways the action of substance P is indirect, via the release of endogenous acetylcholine, whereas this is not so in other species. The present detailed study investigated whether substance P-induced contraction in rabbit isolated bronchus and trachea is due to the release of endogenous acetylcholine or in bronchus is due to histamine release and whether substance P is metabolized by the enzymes enkephalinase and acetylcholinesterase. Isometric contraction to cumulative addition of substance P was measured in the presence of 10(-6) and 10(-4) M atropine, 10(-6) M pyrilamine, 10(-5) M phosphoramidon, or 3 x 10(-7) M neostigmine. Neither atropine nor pyrilamine had any effect on the substance P responses. Phosphoramidon, however, produced a 12-fold shift to the left in the response curve with a decrease in the 50% effective concentration from 7.0 x 10(-8) to 6.1 x 10(-9) M (n = 4 control and 5 treated; P less than 0.05). In contrast, neostigmine at a concentration that produced a sixfold shift to the left in the acetylcholine response curve had no effect on substance P responses. We conclude that, in rabbit airways in vitro, substance P-induced contraction is not mediated by release of endogenous acetylcholine or histamine. In addition, endogenous enkephalinase but not acetylcholinesterase may be involved in the degradation of substance P. Our results show that, in contrast to previous studies in rabbits, the mechanism of action of substance P may resemble that described in humans.

Formyl peptide-induced contraction of human airways in vitro.

Formylmethionylleucylphenylalanine (FMLP) is a synthetic analogue of bacterial chemotactic factors. We studied the contraction of human airway tissue in vitro by FMLP. FMLP induced a concentration-dependent contraction of all bronchial spiral strips studied (n = 45). The maximum tension generated in response to FMLP was 86.6 +/- 7.0% (SE) of the maximum response to histamine. The contraction was not reduced by the histamine H1-receptor antagonist pyrilamine, the cyclooxygenase and lipoxygenase inhibitors indomethacin and BW755C, the muscarinic antagonist atropine, or capsaicin which depletes stores of substance P. The concentration-response curve was shifted to the right by the polypeptide antagonist N-t-BOC-phenylalanylleucylphenylalanylleucylphenylalanine and the leukotriene antagonist FPL 55712. When 2 successive FMLP concentration-response curves were performed the maximum response was significantly reduced from 114.8 +/- 9.1% of the histamine maximum to 39.3 +/- 6.1%. The contraction of human airways in vitro by an agent that is structurally and functionally similar to chemotactic peptides released from bacteria may have important implications in airway disease.

Does the disease state influence the responsiveness of human airways studied in vitro?

Human airway tissue has been used in vitro to study mechanisms of airway disease. However, there has never been a comprehensive study that has looked at the influence of disease on the subsequent in vitro responsiveness of human airways. In this study, we obtained airway tissue from patients who were undergoing resection of the lung for carcinoma. We then compared the airway responsiveness in these tissues and in tissues from patients who had undergone lung transplantation for alpha-1-antitrypsin deficiency, emphysema, or cystic fibrosis with the responsiveness in tissues obtained from donor lungs, i.e., nondiseased. When the relationships between concentration and response were compared, we found that for histamine, electrical field stimulation, levcromakalim, and isoproterenol similar responses could be expected in tissues obtained from all the sources studied. This was not true for acetylcholine in that there were significantly lower responses in tissues from patients with alpha-1-antitrypsin deficiency (P = 0.02; n = 9) or from patients having a lung resected for carcinoma (P = 0.01; n = 6) compared with that of the nondiseased group (n = 6). Similarly, for carbachol, the responses were significantly lower in the alpha-1-antitrypsin deficiency group (P = 0.001; n = 10) and in specimens resected for carcinoma (P = 0.001; n = 6) than in the nondiseased group (n = 9). We conclude that, apart from acetylcholine and carbachol, contractile and relaxant agonists give similar responses when used in human airway tissues from various sources. Our results highlight the importance of stating the source of tissue when human airways are to be studied.

Neurokinin A with K+ channel blockade potentiates contraction to electrical stimulation in human bronchus.

This study investigated the effects of neurokinin A (NKA) on cholinergic neural responses in human bronchus. NKA (0.1 nM) did not alter the contractile response to submaximal electrical field stimulation. However, K+ channel blockade with 4-aminopyridine (4-AP) (0.1 mM) potentiated the response to electrical field stimulation (to 182 +/- 25% of control, n = 4, P less than 0.05) and subsequent addition of NKA in the presence of 4-AP produced further potentiation (to 123 +/- 6% of the response to 4-AP n = 4, P less than 0.05). Neither 4-AP (0.01 or 0.1 mM) nor NKA in the presence of 4-AP potentiated the actions of exogenous acetylcholine but in these experiments 4-AP itself produced a marked direct contractile response. Thus NKA in the presence of K+ channel blockade potentiates cholinergic neural response in human bronchus and this occurs at a prejunctional site.

The effects of salbutamol, theophylline and FPL55712 on leukotriene contraction of guinea pig trachea.

Contraction of guinea pig tracheal smooth muscle was induced by leukotriene C4 or leukotriene D4. The inhibition of the smooth muscle contraction by salbutamol and theophylline was compared with the inhibition by FPL 55712. Salbutamol (5 X 10(-8) - 5 X 10(-7) M) significantly inhibited the leukotriene-induced contraction. The degree of inhibition was greater than that observed with FPL55712 (10(-6) - 10(-4) M). Theophylline (10(-6) - 10(-4) M) did not affect the leukotriene-induced contraction, but enhanced the effect of salbutamol when these agents were combined.

Characterization of contractile prostanoid receptors on human airway smooth muscle.

In human bronchial rings the thromboxane A2 (TxA2) mimetic, U46619, produced cumulative concentration-related contractions up to a maximum of 141 +/- 23% of the response induced by carbachol or acetylcholine. The geometric mean EC50 value was 3.2 X 10(-8) M (95% confidence interval: 1.2, 8.9 X 10(-8) M) (n = 5). Contractions to U46619 were unaffected by atropine (10(-6) M) or verapamil (10(-5) M), but were competitively antagonized by the TxA2 antagonist GR32191 with a pA2 value of 8.40 +/- 0.41. The maximum contractile response to prostaglandin (PG) F2 alpha was smaller (90 +/- 9%, n = 13) and the potency was less (EC50 = 2 X 10(-6) M) than that of U46619. Contractions to PGF2 alpha were also competitively antagonized by GR32191 with a pA2 value of 8.18 +/- 0.08. Concentration-response curves to PGE2 were biphasic, relaxation at concentrations from 10(-9) to 10(-6) M and contraction from 10(-6) to 3 X 10(-5) M. GR32191 10(-7) M inhibited the contractile portion of the response curve in 8 of 11 tissues. Based on these results we conclude that U46619, PGF2 alpha and PGE2 all contract human airways by stimulation of the TxA2 (TP) receptor.

An epithelial-derived factor inhibits contraction in canine perfused bronchial segments.

We have previously reported, using a novel preparation of canine airway segments, that the sensitivity of acetylcholine was greater when applied to the adventitial (outside) surface than the epithelial (inside) surface. The present study investigated if this "barrier-effect" was partly the result of pharmacological modulation by the epithelium. As previously demonstrated, canine airway segments were less sensitive to inside than outside application of acetylcholine (pD(2) 3.0+/-0.4 and 4.5+/-0.4, respectively, P<0.001, n=5). The addition of donor bronchi significantly decreased the sensitivity of the airway segment to outside application of acetylcholine (pD(2) 4.3+/-0.2 and 3.6+/-0.2, respectively, P<0.002, n=4). Indomethacin (2.5 microM) treatment of both the donor bronchi and the airway segment and removal of donor epithelium abolished the rightward shift in the acetylcholine-response curves. In addition, inhibition of cyclooxygenase within the airway segments themselves, but not the donor bronchi, also inhibited the rightward shift in the curves. These results indicate that the donor epithelium is capable of pharmacologically modulating responses of the airway segment to outside applied acetylcholine by producing an epithelial-derived factor, which in turn causes the release of a downstream cyclooxygenase product from within the airway segment.

Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha.

Tumour necrosis factor-alpha (TNF alpha) is implicated in the pathogenesis of asthma; however, little is known of its direct effect on smooth muscle reactivity. We investigated the effect of TNF alpha on the responsiveness of human bronchial tissue to electrical field stimulation in vitro. Incubation of non-sensitized tissue with 1 nM, 3 nM and 10 nM TNF alpha significantly increased responsiveness to electrical field stimulation (113 +/- 8, 110 +/- 4 and 112 +/- 2% respectively) compared to control (99 +/- 2%) (P < 0.05, n = 6). Responses were not increased in sensitized tissue (101 +/- 3% versus 105 +/- 5%, n = 3, P > 0.05) nor were responses to exogenous acetylcholine (93 +/- 4% versus 73 +/- 7%, n = 3, P = 0.38). These results show that TNF alpha causes an increase in responsiveness of human bronchial tissue and that this occurs prejunctionally on the parasympathetic nerve pathway. This is the first report of a cytokine increasing human airway tissue responsiveness.

Cost implications in the management of induction of labour.

For many years the standard treatment of induction of labour has been amniotomy followed by intravenous oxytocin. More recently prostaglandin E2 (PGE2; dinoprostone), in various preparations, has been used to both ripen the cervix before amniotomy and administration of oxytocin, and to induce labour on its own. Since the acquisition cost of PGE2 is approximately 15 times that of oxytocin, it is important to justify the use of PGE2. In this paper, literature from 1970 to 1996 has been reviewed and outcomes following the use of PGE2, plus amniotomy and oxytocin if necessary, have been compared with outcomes following the use of amniotomy plus oxytocin alone. No significant differences in the mode of delivery and no serious adverse effects in mothers or babies were detected. Three economic analyses of these approaches to induction of labour have been reviewed. While under certain conditions there may be some cost savings associated with the use of PGE2, neither of the studies reviewed showed substantial, reliable cost savings. Further research is required to identify the patients who would gain most benefit from the use of PGE2.

Cost-benefit analysis of a Haemophilus influenzae type b meningitis prevention programme in The Philippines.

BACKGROUND: Haemophilus influenzae type b (Hib) meningitis is associated with high mortality and serious sequelae in children under 5 years of age. Vaccines which can prevent this infection are available. OBJECTIVE: To evaluate the costs and benefits of a 3-dose immunisation schedule in Manila, Philippines. PERSPECTIVE: Government and societal perspectives. DESIGN AND PARTICIPANTS: A cost-benefit analysis based on a birth cohort of 100,000 children. The state of health of the cohort with and without a Hib immunisation programme was modelled over a 5-year period. A survey of medical records of patients with Hib in Manila provided data on the extent and cost of sequelae following infection. INTERVENTION: A 3-dose Hib vaccination programme given at ages 2, 3 and 4 months. RESULTS: The model predicted that vaccinating children against Hib meningitis would prevent 553 cases per year in a birth cohort of 100,000, at a cost of 56,200 Philippine pesos (PHP) [$US1,605; 1998 exchange rate] per case (base case assumptions of 90% vaccine efficacy rate, 95 per 100,000 Hib incidence rate, 85% vaccination coverage). Results from the cost-benefit analyses indicated that the saving to the government would be around PHP39 million ($US1.11 million), and the saving to society would be PHP255 million ($US7.28 million). CONCLUSION: There would be a positive economic benefit for the Philippine government and for the Filipino society if a Hib vaccination programme was introduced in Manila.

Differential potency of beclomethasone esters in-vitro on human T-lymphocyte cytokine production and osteoblast activity.

Beclomethasone dipropionate is an inhaled corticosteroid, used for the treatment of asthma. It is metabolised to 17-beclomethasone monopropionate, which has greater affinity for corticosteroid receptors than the parent compound, and to beclomethasone. We investigated the potency of beclomethasone dipropionate, 17-beclomethasone monopropionate and beclomethasone (compared with dexamethasone as a reference steroid) in two different human cell types, peripheral blood mononuclear cells and osteoblasts. We found that beclomethasone dipropionate, 17-beclomethasone monopropionate (EC50 10(-14) M) and beclomethasone (EC50 approx. 10(-12) M) were much more potent than dexamethasone (EC50 10(-8) M) in inhibiting interleukin-5 production by peripheral blood mononuclear cells. In contrast, beclomethasone dipropionate, 17-beclomethasone monopropionate and beclomethasone were equipotent with dexamethasone (EC50 range 0.3-1.2 x 10(-9) M) in affecting several functional assays of osteoblasts (e.g. alkaline phosphatase activity and osteocalcin synthesis). These results show that the relative bioactivities of corticosteroids vary between different human cell types, and that affinities observed in receptor binding assays are not necessarily predictive of the bioactivity in cell populations, such as peripheral blood mononuclear cells and osteoblasts, which are putatively relevant to efficacy and side effects respectively.