Doses Of SP Research Articles

Oral Treatment with SP-333, an Agonist of Guanylate Cyclase-C, Dramatically Ameliorates Morphine-induced Bowel Dysfunction in Rats: Presidential Poster

Purpose: Opioid agonists are commonly used for chronic pain management, but debilitating constipation is a frequent dose-limiting side effect. Guanylate cyclase-C (GC-C) agonists are a new class of drug candidates for the treatment of gastrointestinal (GI) disorders. SP-333, a proteolysis-resistant analog of uroguanylin, activates GC-C to stimulate production of cyclic GMP (cGMP), a second messenger that promotes intestinal secretion and gut motility. Nonclinical toxicology studies have shown that repeated oral doses of SP 333 are well-tolerated in mice and monkeys. SP-333 is currently under clinical development for the treatment of ulcerative colitis. In the current study, the efficacy of SP-333 was assessed in a rat model of opioid-induced bowel dysfunction. Methods: Female CD rats (170-210 g; n=10-12/group) received an intraperitoneal dose of vehicle (water) or 2.5 mg/kg morphine followed by an oral dose of 0 (vehicle), 0.5, 5, or 50 mg/kg of SP-333. A charcoal meal was administered 10 min later, rats were euthanized after an additional 10 min, and GI transit was measured (distance traveled by leading edge of charcoal divided by total length of small intestine). Results: A single dose of morphine significantly reduced GI transit in rats (23.4% in morphine-treated vs 53.3% in vehicle-treated; p≤0.001). SP-333 produced a dose-dependent improvement in gut transit in morphine-treated rats, restoring transit to near normal levels following doses of 5 mg/kg (45.8%) or 50 mg/kg (48.4%) (p≤0.001 for both groups). Conclusion: Treatment with SP-333 accelerated gut transit in morphine-administered rats in a dosedependent manner, possibly via the known cGMP-mediated mode of action. In combination with previously completed toxicology studies, these data support the potential utility of SP 333 and other GC-C agonists as safe oral drug candidates for the treatment of opioid-induced bowel dysfunction. Disclosure - Mr. Kramer, Dr. Palejwala, Dr. Foss and Dr. Shailubhai are employees of Synergy Pharmaceuticals, Inc.Figure

Plasmodium falciparumMutant Haplotype Infection during Pregnancy Associated with Reduced Birthweight, Tanzania

Intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008–October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P. falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed. Of the genotyped parasites, 9.3%, 46.3%, and 44.4% had quadruple or less, quintuple, and sextuple mutated haplotypes, respectively. Mutant haplotypes were unrelated to SP doses. Compared with infections with the less-mutated haplotypes, infections with the sextuple haplotype mutation were associated with lower (359 g) birthweights. Continued use of the suboptimal IPTp-SP regimen should be reevaluated, and alternative strategies (e.g., intermittent screening and treatment or intermittent treatment with safe and effective alternative drugs) should be evaluated.

Antenatal care visit attendance, intermittent preventive treatment and bed net use during pregnancy in Gabon

BackgroundThe World Health Organization (WHO) recommends that intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and insecticide treated bed nets (ITNs) must be provided during antenatal care (ANC) visits for malaria prevention during pregnancy. The aim of this study was to determine the level of ANC attendance and its relationship with IPTp-SP and bed net coverage in Gabonese pregnant women.MethodsThis was a cross-sectional survey performed in 2011 in sentinel sites for malaria: two ANC units (Melen and Owendo) and one delivery unit (CHL). A validated structured questionnaire was used to collect the following data: age, parity, history of the current pregnancy including gestational age at the interview, number of ANC visits already performed, date of first visit, use of malaria preventive measure and details on IPTp-SP administration.ResultsDuring the study, 1030 women were interviewed, 735 at their ANC visit and 295 at the delivery. Their median age was 24[20–29] years and 21.0% were primigravidae. More than 70.0% attended their first ANC visit during the second trimester. Among the 442 women who were at the end of their pregnancy, 71.5% had a correct attendance, at least four ANC visits, most frequently women with no education and older women; IPTp-SP was offered to 84.1% of them and 57.4% received at least two doses. The number of SP doses was correlated to the number of ANC visits. Bed net coverage was 59.0%, not associated with ANC attendance. Among the women with correct ANC attendance, only 49.5% had a complete IPTp-SP course associated with bed net use during pregnancy. In the site where SP administration was supervised, 80% had four ANC visits and 97.4% received a full 2-dose course of IPTp-SP.ConclusionsDespite a high level of correct ANC attendance in Gabon, the goal of 80% of women with 2-dose IPTp-SP during pregnancy is not achieved. Evaluations, training of health workers, as well as surveys from other areas of the country are needed to further measure the implementation and the impact of these strategies.

Prevalence of Dihydrofolate Reductase Gene Mutations in Plasmodium falciparum Isolate from Pregnant Women in Nigeria

We assessed the prevalence of Plasmodium falciparum and the frequency of the dhfr triple mutation that is associated with antifolate drug resistance among P. falciparum isolates obtained from pregnant women in Ilorin, Nigeria. The study included 179 women in the second and third trimester of pregnancy who have been exposed to intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine. Thick and thin blood films and PCR were used for malaria parasite detection. Blood group and hemoglobin concentration were also determined. Mutations in P. falciparum dhfr were analyzed by sequencing DNA obtained from blood spots on filter paper. Prevalence of P. falciparum in the population (PCR corrected) was 44.1% (79/179) with 66.7% and 33.3% in the second and third trimester, respectively. Primigravide (51.3%) were more infected than multigravide (48.7%) but the difference was not statistically significant. Women in blood group A had the highest P. falciparum malaria infection (30.8%). The mean hemoglobin concentration was lower among those infected with malaria parasite. Also, more women with the malaria parasite (38.4%) had anemia compare to those without (21.4%). The prevalence of the P. falciparum dhfr mutant alleles was 64.1%, 61.5%, 38.5%, and 12.8% for I51, R59, N108 and T108, respectively. None of the samples had the L164 mutation. The combined triple dhfr mutation (51 + 59 + 108) in the population was 17.9% (7 of 39). Also, the prevalence of the triple mutant alleles was not significantly associated to the number of doses of SP taken by the women. These findings highlight the need for a regular assessment of IPTp/SP efficacy, and evaluation of possible alternative drugs.

Parasitologic Assessment of Two-Dose and Monthly Intermittent Preventive Treatment of Malaria during Pregnancy with Sulphadoxine-Pyrimethamine (IPTP-SP) in Lagos, Nigeria.

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (IPTP-SP) is a key strategy in the control of malaria in pregnancy. However, reports of increasing level of resistance to SP using nonpregnant populations have made it imperative for the continuous monitoring of the efficacy of SP in pregnant women. This study assessed using microscopy, monthly dosing and the standard two-dose regimen among 259 pregnant women attending antenatal clinics in Lagos, Nigeria that consented 122 in the two-dose arm (Arm A) and 137 in the monthly dose arm (Arm B). Baseline parasitaemia in the two groups was 5 (4.1%) and 3 (2.2%) in Arms A and B, respectively. Few of the women developed parasitaemia after the initial SP dose in Arms A 4 (3.3%) and B 2 (1.5%). However, none of the women had malaria infection after the second dose in both Arms. Although IPTP-SP is suggestive of protecting the women from malaria infection, there was no significant difference observed between the two dosing schemes.

Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali

BackgroundSulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs.MethodsIn a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters.ResultsFourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients.ConclusionDespite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children.

Preventing malaria in pregnancy through community-directed interventions: evidence from Akwa Ibom State, Nigeria

BackgroundDespite massive anti-malaria campaigns across the subcontinent, effective access to intermittent preventive treatment (IPTp) and insecticide-treated nets (ITNs) among pregnant women remain low in large parts of sub-Saharan Africa. The slow uptake of malaria prevention products appears to reflect lack of knowledge and resistance to behavioural change, as well as poor access to resources, and limited support of programmes by local communities and authorities.MethodsA recent community-based programme in Akwa Ibom State, Nigeria, is analysed to determine the degree to which community-directed interventions can improve access to malaria prevention in pregnancy. Six local government areas in Southern Nigeria were selected for a malaria in pregnancy prevention intervention. Three of these local government areas were selected for a complementary community-directed intervention (CDI) programme. Under the CDI programme, volunteer community-directed distributors (CDDs) were appointed by each village and kindred in the treatment areas and trained to deliver ITNs and IPTp drugs as well as basic counseling services to pregnant women.FindingsRelative to women in the control area, an additional 7.4 percent of women slept under a net during pregnancy in the treatment areas (95% CI [0.035, 0.115], p-value < 0.01), and an additional 8.5 percent of women slept under an ITN after delivery and prior to the interview (95% CI [0.045, 0.122], p-value < 0.001). The effects of the CDI programme were largest for IPTp adherence, increasing the fraction of pregnant women taking at least two SP doses during pregnancy by 35.3 percentage points [95% CI: 0.280, 0.425], p-value < 0.001) relative to the control group. No effects on antenatal care attendance were found.ConclusionThe presented results suggest that the inclusion of community-based programmes can substantially increase effective access to malaria prevention, and also increase access to formal health care access in general, and antenatal care attendance in particular in combination with supply side interventions. Given the relatively modest financial commitments they require, community-directed programmes appear to be a cost-effective way to improve malaria prevention; the participatory approach underlying CDI programmes also promises to strengthen ties between the formal health sector and local communities.

Substance P (SP) Contributes To Rapidly Adapting Receptor (RAR) Activity In High Altitude Pulmonary Edema (HAPE)

AimsTo investigate whether there is a change in i) basal RAR activity and ii) their responses to SP, in rabbits with HAPE.MethodsExperiments were performed in anesthetized, artificially ventilated and thoracotomized rabbits. After routine cannulations, the RAR activity was recorded from cervical vagus nerve. Increasing doses of SP were administered into the right atrium in control rabbits (C) breathing room air (n= 6) and in rabbits with HAPE (n= 6). To produce HAPE, rabbits were placed in a high altitude simulation chamber ‐ 15,000 feet, 36 hrs. In both the groups, SP doses were repeated after the administration of NK‐1 receptor antagonist, CP‐96345 (400 nmol/kg, Pfizer, Croton, USA).ResultsThe basal RAR activity in C was 6.34±0.46 impulses/breath and it increased to 10.0±0.64 impulses/breath (p&lt;0.001) in HAPE. SP stimulated the RARs in both the groups. However, in HAPE, the RARs were stimulated even by sub‐threshold doses of SP. CP‐96345 attenuated the RAR activity in C but not in HAPE. RAR response to SP in C and HAPE groups. RAR activity in % Groups After SP (μg/kg) 0.02 0.04 0.08 Before CP‐96345 C 16.22±4.99 28.44±7.00 48.95±9.92 HAPE 51.14±5.10 *** 54.83±3.77** Not done After CP‐96345 C 18.10±8.59 24.44±9.27 20.58±4.98 HAPE 38.55±8.87 56.50±6.11* Not done RAR activity expressed as a percentage of their respective basal activities. p&lt;0.05, p&lt;0.01 and p&lt;0.001, compared with the corresponding response in C. Conclusion1.HAPE stimulates RARs. 2. The RARs do not show adaptation to this stimulus. 3. Endogenous SP released during HAPE sensitizes the RARs to exogenous SP. Funded by DIPAS, Delhi.

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso: effect of adding a third dose to the standard two-dose regimen on low birth weight, anaemia and pregnancy outcomes

BackgroundIntermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW) and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome.MethodsPregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2) or 3 doses (SP3) of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW (<2500 g), severe anaemia (Hb < 8 g/dL) and premature birth was analysed using intention-to-treat (ITT) and per-protocol (PP) analysis.ResultsData from 1274 singleton pregnancies were analysed (641 in the SP3 and 633 in the SP2 group). The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24) in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 - 0.90). The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance.ConclusionThe risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal.

Efficacy of intermittent preventive treatment with sulfadoxine–pyrimethamine on placental parasitemia in pregnant women in midwestern Nigeria

Objective To assess the effect of intermittent preventive treatment with sulfadoxine and pyrimethamine (IPT-SP) on placental parasitemia and maternal and perinatal outcome. Methods We compared placental malaria parasitemia during pregnancy and pregnancy outcome in 2 groups of women receiving antenatal care at University of Benin Teaching Hospital. One group was prophylactically treated with IPT-SP and the other was not treated. Results The parasitemia rates for peripheral, placental, and cord blood were 11.9%, 11.4%, and 2.7% in the IPT-SP group (n = 370) and 19.1%, 22.6%, and 6.2% in the control group (n = 371) ( P = 0.006, P = 0.002, and P = 0.02, respectively). The treatment reduced the odds of placental parasitemia by 37% (OR 0.63; 95% CI, 0.48–0.81). Peripheral ( P = 0.002) and placental ( P = 0.001) parasitemia were significantly reduced in the subgroup of women who took 2 or 3 doses of SP. Fewer women (16.2%) in the IPT-SP group than the control group (23.7%) had symptomatic malaria. Anemia at delivery was significantly lower in the IPT-SP group (10.8 vs 1.6%). The risks of abortion, preterm delivery, and low birth weight were also significantly lower in the IPT-SP group. Conclusion IPT-SP is effective in preventing placental parasitemia, and reduces rates of malaria, maternal anemia, abortion, preterm delivery and low birth weight among pregnant women.

Protective Efficacy of Intermittent Preventive Treatment of Malaria in Infants (IPTi) Using Sulfadoxine-Pyrimethamine and Parasite Resistance

BackgroundIntermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi) is recommended by WHO for implementation in settings where resistance to SP is not high. Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance.Methods and ResultsWe analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50km of the trial sites. We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi. This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times. However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively.ConclusionsA significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose. An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias. It was not possible to define a more definite relationship based on the data available from these trials.

Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women

BackgroundIn sub-Saharan Africa, Plasmodium falciparum malaria in pregnancy presents an enormous diagnostic challenge. The epidemiological and clinical relevance of the different types of malaria diagnosis as well as risk factors associated with malaria infection at delivery were investigated.MethodIn a cross-sectional survey, 306 women reporting for delivery in the Mutenegene maternity clinic, Fako division, South West province, Cameroon were screened for P. falciparum in peripheral blood, placental blood and placental tissue sections by microscopy. Information relating to the use of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine, history of fever attack, infant birth weights and maternal anaemia were recorded.ResultsAmong these women, P. falciparum infection was detected in 5.6%, 25.5% and 60.5% of the cases in peripheral blood, placental blood and placental histological sections respectively. Placental histology was more sensitive (97.4%) than placental blood film (41.5%) and peripheral blood (8.0%) microscopy. In multivariate analysis, age (≤ 20 years old) (OR = 4.61, 95% CI = 1.47 – 14.70), history of fever attack (OR = 2.98, 95% CI = 1.58 – 5.73) were significant risk factors associated with microscopically detected parasitaemia. The use of ≥ 2 SP doses (OR = 0.18, 95% CI = 0.06 – 0.52) was associated with a significant reduction in the prevalence of microscopic parasitaemia at delivery. Age (>20 years) (OR = 0.34, 95% CI = 0.15 – 0.75) was the only significant risk factor associated with parasitaemia diagnosed by histology only in univariate analysis. Microscopic parasitaemia (OR = 2.74, 95% CI = 1.33–5.62) was a significant risk factor for maternal anaemia at delivery, but neither infection detected by histology only, nor past infection were associated with increased risk of anaemia.ConclusionPlacenta histological examination was the most sensitive indicator of malaria infection at delivery. Microscopically detected parasitaemia was associated with increased risk of maternal anaemia at delivery, but not low-grade parasitaemia detected by placental histology only.

Individual efficacy of intermittent preventive treatment with sulfadoxine–pyrimethamine in primi‐ and secundigravidae in rural Burkina Faso: impact on parasitaemia, anaemia and birth weight

To assess the efficacy at individual level of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) in primi- and secundigravidae in rural Burkina Faso. Data of 1441 women enrolled in a health centre randomized trial and delivering a live-singleton between September 2004 and October 2006 were analysed at individual level. Prevalence of peripheral and placental parasitaemia, anaemia (PCV <33%), low-birth weight (<2500 g; LBW), mean packed cell volume (PCV) and birth weight were compared in relation to the number of directly observed SP doses. Two or more doses of SP significantly reduced the risk of placental parasitaemia [adjusted odds ratio (AOR) = 0.04, 95%CI = 0.003-0.60, P = 0.023] and anaemia at delivery (AOR = 0.31, 95%CI = 0.18-0.52, P < 0.001). IPTp was associated with reduced risk of LBW in primigravidae (AOR = 0.11, 95%CI = 0.07-0.17, P < 0.001) but not secundigravidae (AOR = 0.70, 95%CI = 0.26-1.91, P = 0.452). For each increment in number of SP doses mean PCV increased by 1.0% (95%CI = 0.4-1.7, P = 0.005) at 32 weeks gestation, by 1.2% (95%CI = 0.2-2.2, P = 0.025) at delivery and mean birth weight by 220 g (95%CI = 134-306 P < 0.001) in primigravidae and by 102 g (95%CI = 55-148, P = 0.001) in secundigravidae. The risk of malaria infection was significantly reduced by IPTp with SP in primi- and secundigravidae in rural Burkina Faso. The impact on clinical outcomes is lower and mainly limited to primigravidae for LBW. Incomplete uptake of IPTp-SP and limited effect in low risk groups together may substantially dilute the measurable impact of effective interventions. This needs to be taken into account when evaluating interventions at community level.

A community effectiveness trial of strategies promoting intermittent preventive treatment with sulphadoxine-pyrimethamine in pregnant women in rural Burkina Faso

BackgroundIntermittent preventive treatment with sulphadoxine-pyrimethamine for pregnant women (IPTp-SP) is currently being scaled up in many countries in sub-Saharan Africa. Despite high antenatal clinic (ANC) attendance, coverage with the required two doses of SP remains low. The study investigated whether a targeted community-based promotion campaign to increase ANC attendance and SP uptake could effectively improve pregnancy outcomes in the community.MethodsBetween 2004 and 2006 twelve health centres in Boromo Health District, Burkina Faso were involved in this study. Four were strategically assigned to community promotion in addition to IPTp-SP (Intervention A) and eight were randomly allocated to either IPTp-SP (Intervention B) or weekly chloroquine (Control). Primi- and secundigravidae were enrolled at village level and thick films and packed cell volume (PCV) taken at 32 weeks gestation and at delivery. Placental smears were prepared and newborns weighed. Primary outcomes were peripheral parasitaemia during pregnancy and at delivery, placental malaria, maternal anaemia, mean and low birth weight. Secondary outcomes were the proportion of women with ≥ 3 ANC visits and ≥ 2 doses of SP. Intervention groups were compared using logistic and linear regression with linearized variance estimations to correct for the cluster-randomized design.ResultsSP uptake (≥ 2 doses) was higher with (Intervention A: 70%) than without promotion (Intervention B: 49%) (OR 2.45 95%CI 1.25–4.82 p = 0.014). Peripheral (33.3%) and placental (30.3%) parasite rates were significantly higher in the control arm compared to Intervention B (peripheral: 20.1% OR 0.50 95%CI 0.37–0.69 p = 0.001; placental: 20.5% OR 0.59 95%CI 0.44–0.78 p = 0.002) but did not differ between Intervention A (17.4%; 18.1%) and Intervention B (20.1; 20.5%) (peripheral: OR 0.84 95%CI 0.60–1.18 p = 0.280; placental: OR 0.86 95%CI 0.58–1.29 p = 0.430). Mean PCV and birth weight and prevalence of anaemia and low birth weight did not differ between study arms.ConclusionThe promotional campaign resulted in a major increase in IPTp-coverage, with two thirds of women at delivery having received ≥ 2 SP. Despite lower prevalence of malaria infection this did not translate into a significant difference in maternal anaemia or birth weight. This data provides evidence that, as with immunization programmes, extremely high coverage is essential for effectiveness. This critical threshold of coverage needs to be defined, possibly on a regional basis.

Are probiotics beneficial for health?

In August, experts (Gibson, McFarlane and Edwards, Society for Applied Microbiology press briefing) warned that many probiotics contain far fewer ‘friendly bacteria’ than claimed. This stimulated a number of headlines questioning the effectiveness of probiotic products: ‘Why up to half of all probiotics don’t work’ ( Daily Mail , August 2006), and ‘Half of probiotic drinks fail bacteria health test’ ( Guardian , August 2006). The news stories specifically referred to yogurt drinks that contain live bacteria, which are reported to help change the balance of intestinal bacteria, thereby helping maintain healthy digestive and immune systems. According to Gibson, at least 10 million bacteria per dose from the Bifidobacteria or Lactobacillus sp . groups are needed for health benefits; yet many products do not contain the adequate dose or the right strains of bacteria. An adequate level of viable bacteria in a probiotic product, and an appropriate daily dose, are critical to achieve a health benefit (Lin 2003). Consumers were advised to carefully check product labels to ensure that they contain the correct dose of Bifidobacteria or Lactobacillus sp .; Gibson also advised that the larger manufacturers are more reliable.

Efficacies of artesunate plus either sulfadoxine–pyrimethamine or amodiaquine, for the treatment of uncomplicated,Plasmodium falciparummalaria in eastern Sudan

Artemisinin-based combination therapy (ACT) is increasingly being adopted as the first-line treatment for malaria in sub-Saharan Africa. In September-November 2005, in New Halfa, eastern Sudan, the efficacy of artesunate-sulfadoxine-pyrimethamine (AS-SP) for the treatment of uncomplicated, Plasmodium falciparum was compared with that of artesunate-amodiaquine (AS-AQ). The artesunate was given at 4 mg/kg. day on days 0-2, with either a single dose of SP (25 mg sulfadoxine/kg) given on day 0, or AQ, at 10 mg/kg. day, given on days 0-2. Eighty-two of the patients treated (40 given AS-SP and 42 given AS-AQ) completed the 28 days of follow-up. On day 3 all the patients were afebrile and only one patient, in the AS-AQ group, was still parasitaemic. AS-SP appeared slightly more efficacious than AS-AQ but the differences were not statistically significant. Only one patient (2.5%) given AS-SP but four (9.5%) of those given AS-AQ were initially considered to be late treatment and parasitological failures, with all other patients showing an adequate treatment response. The PCR-corrected frequencies of cure were 97.5% for AS-SP and 95.2% for AS-AQ (P>0.05). No gametocytaemias were observed during the follow-up and, although mild adverse effects (nausea, vomiting, abdominal pain, dizziness and/or rash) were detected in 14 patients, they occurred at the same frequency in each treatment arm. It therefore appears that the AS-SP and AS-AQ combinations were both effective and safe for the treatment of uncomplicated, P. falciparum malaria in eastern Sudan.

Short course of quinine plus a single dose of sulfadoxine/pyrimethamine for Plasmodium falciparum malaria

Quinine remains the treatment of choice in hospitalized malaria cases; however, adverse reactions and the long treatment duration of 7 days often hamper its adequate use. Shortening the treatment by adding sulfadoxine/pyrimethamine may enhance compliance and reduce side effects. We aimed to assess the efficacy of a 3-day course of quinine plus a single dose of sulfadoxine/pyrimethamine for the treatment of non-severe hospitalized malaria cases in Lambaréné, Gabon. Fifty children aged between 2 and 7 years received quinine dihydrochloride (12 mg/kg every 12 hours for 72 hours), and then a single dose of oral SP (500 mg/25 mg tablet) was given according to weight category. The children were hospitalized for the duration of the treatment and until two consecutive blood smears were negative for malaria parasites. The follow-up period lasted 28 days. Parasites were cleared after 66 hours (SD: 15 hours) and the fever after 46 hours (SD: 24 hours). All patients evaluable by day 28 were negative for malaria parasites (100% efficacy rate, 95% CI: 0.92-1). Only two patients out of 49 had gametocytemia on days 7 and 14. There was no adverse event probably or possibly attributable to the study drugs. A very high efficacy can be reached using a 3-day course of quinine plus a single dose of sulfadoxine/pyrimethamine for the treatment of non-severe hospitalized malaria cases in our study area.

Substance P Stimulates Cyclooxygenase-2 and Prostaglandin E2 Expression through JAK-STAT Activation in Human Colonic Epithelial Cells

Substance P (SP) via its neurokinin-1 receptor (NK-1R) regulates several gastrointestinal functions. We previously reported that NK-1R-mediated chloride secretion in the colon involves formation of PG. PGE2 biosynthesis is controlled by cyclooxygenase-1 (COX-1) and COX-2, whose induction involves the STATs. In this study, we examined whether SP stimulates PGE2 production and COX-2 expression in human nontransformed NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) and identified the pathways involved in this response. SP exposure time and dose dependently induced an early (1-min) phosphorylation of JAK2, STAT3, and STAT5, followed by COX-2 expression and PGE2 production by 2 h. Pharmacologic experiments showed that PGE2 production is dependent on newly synthesized COX-2, but COX-1 protein. Inhibition of protein kinase Ctheta (PKCtheta), but not PKCepsilon and PKCdelta, significantly reduced SP-induced COX-2 up-regulation, and JAK2, STAT3, and STAT5 phosphorylation. Pharmacological blockade of JAK inhibited SP-induced JAK2, STAT3, and STAT5 phosphorylation; COX-2 expression; and PGE2 production. Transient transfection with JAK2 short-interferring RNA reduced COX-2 promoter activity and JAK2 phosphorylation, while RNA interference of STAT isoforms showed that STAT5 predominantly mediates SP-induced COX-2 promoter activity. Site-directed mutation of STAT binding sites on the COX-2 promoter completely abolished COX-2 promoter activity. Lastly, COX-2 expression was elevated in colon of mice during experimental colitis, and this effect was normalized by administration of the NK-1R antagonist CJ-12,255. Our results demonstrate that SP stimulates COX-2 expression and PGE2 production in human colonocytes via activation of the JAK2-STAT3/5 pathway.

Anxiolytic-like effects of substance P fragment (SP 1–7) in non-human primates ( Callithrix penicillata)

The behavioral effects of the amino (N)-terminal fragment of substance P (SP 1–7) on the marmoset ( Callithrix penicillata) predator confrontation test of fear/anxiety were investigated. The test apparatus consisted of a figure-eight maze with three parallel arms interconnected at each extremity to a perpendicular arm. A taxidermized oncilla cat ( Felis tigrina) was placed outside the maze facing one of its corners. Subjects were submitted to seven 30 min maze habituation trials (HTs), in the absence of the ‘predator’, and then to six 30 min treatment trials (TTs), in the presence of the ‘predator’, consisting of four doses of SP 1–7 (5, 50, 250 and 500 μg/kg; IP), saline and sham injection. SP 1–7 treatment reversed, in a dose-dependent way, the fear-induced avoidance behavior due to the predator’s presence and increased the frequency of exploratory behaviors. Locomotor activity decreased during successive HTs, yet increased after all SP 1–7 treatments. These results indicate that systemic administration of SP 1–7 produces anxiolytic-like effects in marmosets tested in the predator confrontation model of fear/anxiety.

Tachykinins via Tachykinin NK(2) receptor activation mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs.

1. Acute exposure to ozone is known to cause airway hyperresponsiveness, which, at least in part, seems to result from an increase in the permeability of the airway mucosa. Recently, we demonstrated that depletion of sensory neuropeptides inhibits the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. The aim of this study was to determine whether tachykinins mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. 2. Anaesthetized guinea-pigs were exposed to either 3 p.p.m. ozone or filtered air for 30 min. Immediately after exposure, a tracheal segment was isolated in vivo and administered with horseradish peroxidase (HRP). The permeability was assessed by monitoring the appearance of HRP in the blood. 3. A low dose of NKA increased the permeability of the tracheal mucosa, whereas a low dose of SP was without effect. Low and high doses of the selective NK(3) receptor agonist, senktide, were also without effect. The effect of a low dose of NKA was abolished by the NK(2) receptor antagonist, SR-48,968. A high dose of SP increased the permeability in a manner reversible by the NK(1) receptor antagonist, CP-96,345. 4. Pretreatment with SR-48,968 completely inhibited the ozone-induced increase in the permeability, whereas CP-96,345 had no effect. 5. It is thus concluded that endogenous tachykinins mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs mainly via NK(2) receptor activation.