Corrected QT interval in hospitalized patients with coronavirus disease 2019: Focus on drugs therapy.

ABSTRACT: Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.

Interventions for cutaneous disease in systemic lupus erythematosus.

BACKGROUND: Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many interventions are used to treat SLE with varying efficacy, risks, and benefits. OBJECTIVES: To assess the effects of interventions for cutaneous disease in SLE. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, Wiley Interscience Online Library, and Biblioteca Virtual em Saude (Virtual Health Library). We updated our search in September 2020, but these results have not yet been fully incorporated. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions for cutaneous disease in SLE compared with placebo, another intervention, no treatment, or different doses of the same intervention. We did not evaluate trials of cutaneous lupus in people without a diagnosis of SLE. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were complete and partial clinical response. Secondary outcomes included reduction (or change) in number of clinical flares; and severe and minor adverse events. We used GRADE to assess the quality of evidence. MAIN RESULTS: Sixty-one RCTs, involving 11,232 participants, reported 43 different interventions. Trials predominantly included women from outpatient clinics; the mean age range of participants was 20 to 40 years. Twenty-five studies reported baseline severity, and 22 studies included participants with moderate to severe cutaneous lupus erythematosus (CLE); duration of CLE was not well reported. Studies were conducted mainly in multi-centre settings. Most often treatment duration was 12 months. Risk of bias was highest for the domain of reporting bias, followed by performance/detection bias. We identified too few studies for meta-analysis for most comparisons. We limited this abstract to main comparisons (all administered orally) and outcomes. We did not identify clinical trials of other commonly used treatments, such as topical corticosteroids, that reported complete or partial clinical response or numbers of clinical flares. Complete clinical response Studies comparing oral hydroxychloroquine against placebo did not report complete clinical response. Chloroquine may increase complete clinical response at 12 months' follow-up compared with placebo (absence of skin lesions) (risk ratio (RR) 1.57, 95% confidence interval (CI) 0.95 to 2.61; 1 study, 24 participants; low-quality evidence). There may be little to no difference between methotrexate and chloroquine in complete clinical response (skin rash resolution) at 6 months' follow-up (RR 1.13, 95% CI 0.84 to 1.50; 1 study, 25 participants; low-quality evidence). Methotrexate may be superior to placebo with regard to complete clinical response (absence of malar/discoid rash) at 6 months' follow-up (RR 3.57, 95% CI 1.63 to 7.84; 1 study, 41 participants; low-quality evidence). At 12 months' follow-up, there may be little to no difference between azathioprine and ciclosporin in complete clinical response (malar rash resolution) (RR 0.83, 95% CI 0.46 to 1.52; 1 study, 89 participants; low-quality evidence). Partial clinical response Partial clinical response was reported for only one key comparison: hydroxychloroquine may increase partial clinical response at 12 months compared to placebo, but the 95% CI indicates that hydroxychloroquine may make no difference or may decrease response (RR 7.00, 95% CI 0.41 to 120.16; 20 pregnant participants, 1 trial; low-quality evidence). Clinical flares Clinical flares were reported for only two key comparisons: hydroxychloroquine is probably superior to placebo at 6 months' follow-up for reducing clinical flares (RR 0.49, 95% CI 0.28 to 0.89; 1 study, 47 participants; moderate-quality evidence). At 12 months' follow-up, there may be no difference between methotrexate and placebo, but the 95% CI indicates there may be more or fewer flares with methotrexate (RR 0.77, 95% CI 0.32 to 1.83; 1 study, 86 participants; moderate-quality evidence). Adverse events Data for adverse events were limited and were inconsistently reported, but hydroxychloroquine, chloroquine, and methotrexate have well-documented adverse effects including gastrointestinal symptoms, liver problems, and retinopathy for hydroxychloroquine and chloroquine and teratogenicity during pregnancy for methotrexate. AUTHORS' CONCLUSIONS: Evidence supports the commonly-used treatment hydroxychloroquine, and there is also evidence supporting chloroquine and methotrexate for treating cutaneous disease in SLE. Evidence is limited due to the small number of studies reporting key outcomes. Evidence for most key outcomes was low or moderate quality, meaning findings should be interpreted with caution. Head-to-head intervention trials designed to detect differences in efficacy between treatments for specific CLE subtypes are needed. Thirteen further trials are awaiting classification and have not yet been incorporated in this review; they may alter the review conclusions.

Insights in Chloroquine Action: Perspectives and Implications in Malaria and COVID-19.

Malaria is a threat to human mankind and kills about half a million people every year. On the other hand, COVID-19 resulted in several hundred thousand deaths since December 2019 and remains without an efficient and safe treatment. The antimalarials chloroquine (CQ) and its analog, hydroxychloroquine (HCQ), have been tested for COVID-19 treatment, and several conflicting evidence has been obtained. Therefore, the aim of this review was to summarize the evidence regarding action mechanisms of these compounds against Plasmodium and SARS-CoV-2 infection, together with cytometry applications. CQ and HCQ act on the renin angiotensin system, with possible implications on the cardiorespiratory system. In this context, flow and image cytometry emerge as powerful technologies to investigate the mechanism of therapeutic candidates, as well as for the identification of the immune response and prognostics of disease severity. Data from the large randomized trials support the conclusion that CQ and HCQ do not provide any clinical improvements in disease severity and progression of SARS-CoV-2 patients, as well as they do not present any solid evidence of increased serious side effects. These drugs are safe and effective antimalarials agents, but in SARS-CoV-2 patients, they need further studies in the context of clinical trials. © 2020 International Society for Advancement of Cytometry.

Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity.

Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations.

An in vivo drug screening model using glucose-6-phosphate dehydrogenase deficient mice to predict the hemolytic toxicity of 8-aminoquinolines.

Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.

A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity.

Chloroquine (CQ) is a widely prescribed anti-malarial agent and is also prescribed to treat autoimmune diseases. Clinical treatment with CQ is often accompanied by serious side effects such as hepatitis and retinopathy. As a weak base, CQ accumulates in intracellular acidic organelles, raises the pH, and induces osmotic swelling and permeabilization of acidic organelles, which account for CQ-induced cytotoxicity. We reported previously that CQ treatment caused α-tocopherol transfer protein (α-TTP), a gene product of familial vitamin E deficiency, to change its location from the cytosol to the surface of acidic organelles. Here we show that α-TTP plays a novel role in protecting against CQ toxicity both in vitro and in vivo. In the presence of CQ, rat hepatoma McARH7777 cells, which do not express α-TTP endogenously, showed more severe cytotoxicity, such as larger vacuolation of acidic organelles and caspase activation, than α-TTP transfectant cells. Similarly, α-TTP knockout mice showed more severe CQ toxicity, such as hepatotoxicity and retinopathy, than wild-type mice. These effects were not ameliorated by vitamin E supplementation. In contrast to bafilomycin A1 treatment, which prevents CQ accumulation in cells by raising the pH of acidic organelles, α-TTP expression prevented CQ accumulation without affecting the pH of acidic organelles. Taken together, our data suggest that α-TTP protects against CQ toxicity by preventing CQ accumulation in acidic organelles through a mechanism distinct from vitamin E transport.

Therapeutic alternatives for chronic urticaria: an evidence-based review, part 1.

OBJECTIVE: To evaluate the use of alternative therapies for chronic urticaria refractory to first-line treatments in an evidence-based manner. DATA SOURCES: MEDLINE searches were performed cross-referencing urticaria with the names of multiple therapies. Articles were then reviewed for additional citations. Articles published after 1950 were considered. STUDY SELECTION: All articles, including case reports, were reviewed for soundness and relevance. RESULTS: Experience has been reported for a wide variety of alternative therapies in the treatment of chronic idiopathic and physical urticarias. Evidence for most agents is limited to anecdotal reports. The second-line therapies reviewed are also categorized based on criteria of safety, efficacy, convenience, and cost, in relation to the first-line antihistamines. CONCLUSIONS: Alternative agents should be considered in patients with chronic urticaria who are both severely affected and unresponsive to antihistamines. Although monitoring for toxicity is important in management with many alternative agents, safety is favorable compared with corticosteroids.

Adding artesunate to sulphadoxine-pyrimethamine greatly improves the treatment efficacy in children with uncomplicated falciparum malaria on the coast of Benin, West Africa.

BACKGROUND: Benin has recently shifted its national antimalarial drug policy from monotherapies to combinations containing artemisinin derivatives. When this decision was taken, the available information on alternatives to chloroquine and sulphadoxine-pyrimethamine, the first- and second-line treatment, was sparse. METHODS: In 2003 - 2005, before the drug policy change, a randomized, open-label, clinical trial was carried out on the efficacy of chloroquine, and sulphadoxine-pyrimethamine alone or combined with artesunate, with the aim of providing policy makers with the information needed to formulate a new antimalarial drug policy. Children between six and 59 months of age, with uncomplicated malaria and living in the lagoon costal area in southern Benin, were randomly allocated to one of the three study arms and followed up for 28 days. RESULTS: Treatment failure (PCR corrected) was significantly lower in the artesunate + sulphadoxine-pyrimethamine group (4/77, 5.3%) than in chloroquine group(51/71, 71.8%) or the sulphadoxine-pyrimethamine alone group (30/70, 44.1%) (p < 0.001). Despite high sulphadoxine-pyrimethamine failure, its combination with artesunate greatly improved treatment efficacy. CONCLUSION: In Benin, artesunate + sulphadoxine-pyrimethamine is efficacious and could be used when the recommended artemisinin-based combinations (artemether-lumefantrine and amodiaquine-artesunate) are not available. However, because sulphadoxine-pyrimethamine is also used in pregnant women as intermittent preventive treatment, its combination with artesunate should not be widely employed in malaria patients as this may compromise the efficacy of intermittent preventive treatment.

Effect of chloroquine on strips of non-pregnant and pregnant mice uteri in-vitro.

Chloroquine (CQ) remains the household drug for the treatment of malaria especially among pregnant women. However, there are reports that CQ inhibits the contractile process in non-pregnant rat's uterus. The aim of this study is to compare responses to CQ between non-pregnant and pregnant mice and identify some mechanisms involved. Experiments were carried out in non-pregnant and pregnant mice pretreated 24 hours before with 1.5 mg/kg-body weight stilboesterol given orally. Strips of uterine smooth muscle, approximately 5 mm in diameter, were mounted in a 20 ml organ bath containing De Jalon solution bubbled with a 95% O2-5% CO2 gas mixture. Responses of the strips to graded concentration of acetylcholine (ACh) (10(-9) to 10(-5) mol/L), oxytocin (OXY) (10(-5) to 10(-2) IU/ml) and CQ (10(-6) to 4 x 10(-4) mol/L) were investigated. The strips were then incubated in 4 x 10(-4) mol/L CQ for 15 mins and the cumulative dose responses for OXY were repeated. To investigate mechanism of action, the strips were incubated for 15 mins in N(w)-nitro L-arginine methyl ester (L-NAME) and the cumulative responses to CQ repeated. Each investigation was carried out in fresh tissue mounted on Grass Model FT03 force transducer coupled unto a 4-channel Grass Model 7D Polygraph. CQ (low to moderate level), ACh and OXY led to increases in contractile responses in the uteri. There were greater contractile responses in non-pregnant than pregnant mice to CQ and ACh. At high doses, CQ had an inhibitory effect on the uterine contraction. Incubating in CQ led to abolition of contractile responses to OXY and ACh. In the presence of L-NAME, inhibitory effect of CQ at high doses was attenuated in pregnant mice only. The results suggest that CQ at high doses inhibits contractile responses in non-pregnant and pregnant mice. Enhanced nitric oxide bioactivity attenuated this inhibitory effect.

Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children.

BACKGROUND: Artemisinin-based combination antimalarials are currently considered effective alternatives for the treatment of malaria in Africa, but there are few studies of such combinations in Nigerian children. We assessed the safety, treatment efficacy and effects on gametocyte carriage of the combination of artesunate plus amodiaquine and chloroquine plus pyrimethamine-sulfadoxine in children. METHODS: We evaluated 153 children who were aged 12 years or younger who had uncomplicated Plasmodium falciparum malaria. Patients were randomly assigned a combination of artesunate (4 mg/kg of body weight daily for 3 days) plus amodiaquine (30 mg/kg over 3 days), or chloroquine (25 mg/kg over 3 days) plus pyrimethamine-sulfadoxine (25 mg/kg of the sulfadoxine component at presentation). The primary endpoints were the proportions of children with adequate clinical and parasitological response, late parasitological failure, late clinical failure and early treatment failure. The parasitological cure rates on days 14-28 were also used as the primary endpoints. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. All children treated with artesunate plus amodiaquine had adequate clinical and parasitological response (ACPR), while all but five children treated with chloroquine plus pyrimethamine-sulfadoxine had similar response. Fever clearance times were similar in the two treatment groups. However, the proportion of patients whose parasitaemia cleared by day 2 was significantly higher (100 vs. 50%, P = 0.00001) and parasite clearance was significantly faster (1.7 +/- 0.4 vs. 2.5 +/- 0.8 days, P = 0.0001) in children treated with artesunate plus amodiaquine. The cure rates on days 21 (100%vs. 94%, P = 0.03) and 28 (100%vs. 90%, P = 0.003) were also significantly higher in children treated with artesunate plus amodiaquine than in those treated with chloroquine plus pyrimethamine-sulfadoxine. Overall, a significantly higher proportion of children treated with chloroquine plus pyrimethamine-sulfadoxine carried gametocytes at least once during follow-up compared with those treated with artesunate plus amodiaquine [5 of 50 (10%) vs. 1 of 103 (0.97%), P = 0.01]. CONCLUSION: The combination of artesunate plus amodiaquine is therapeutically superior to a combination of chloroquine plus pyrimethamine-sulfadoxine, and significantly reduced gametocyte carriage following treatment.

Efficacy of artesunate plus chloroquine for the treatment of uncomplicated malaria in children in Burkina Faso: a double-blind, randomized, controlled trial.

Chloroquine (CQ)-resistant Plasmodium falciparum is compromising malaria control in Africa. Combining artesunate (AS) with standard antimalarial drugs increases cure rates and may delay drug resistance. We compared the safety and efficacy of CQ alone and CQ combined with AS (CQ-AS) for treating uncomplicated P. falciparum malaria in Burkina Faso between August 1999 and August 2000. Chloroquine (25 mg/kg over 3 d) combined with AS or placebo (4 mg/kg/d for 3 d) was administered to 300 children aged 6 to 59 months in a randomized, double-blind study. Follow-up extended over 28 d. No adverse drug reactions were recorded. By day 14, parasites were cleared in 120/147 (81.6%) CQ AS-treated children compared with 53/143 (37.1%) CQ-treated children (odds ratio [OR] = 7.55, 95% CI 4.27-13.43, P < 0.001). Corresponding rates for day 28 were 71/145 (49.0%) vs. 27/142 (19.0%) (OR= 4.09, 95% CI 2.33-7.21, P < 0.001). Children who received CQ-AS had significantly faster parasite and fever clearance. Despite the beneficial effects of adding AS, the high failure rate at day 28 of CQ-AS precludes its use as the first-line regimen for treating CQ-resistant P. falciparum in Burkina Faso.

Atovaquone and proguani hydrochloride compared with chloroquine or pyrimethamine/sulfodaxine for treatment of acute Plasmodium falciparum malaria in Peru.

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] vs. 8% [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

A randomized, double-blind, parallel-group, comparative safety, and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in India.

In India, treatment of acute, uncomplicated Plasmodium falciparum malaria is becoming increasingly difficult due to resistance to chloroquine, thus there is a need for new antimalarial drugs. CGP 56697 (co-artemether), a new drug, is a combination of artemether and lumefantrine in a single oral formulation (one tablet = 20 mg of artemether plus 120 mg of lumefantrine). In a double-blind study, 179 patients with acute uncomplicated P. falciparum malaria were randomly assigned to receive either CGP (n = 89) given as a short course of 4 x 4 tablets over a 48-hr period or chloroquine (n = 90) given as four tablets (one tablet = 150 mg of chloroquine base) initially, followed by two tablets each at 6-8, 24, and 48 hr. Due to a death in the chloroquine group and a decrease in the chloroquine cure rate to < 50% (based on the blinded overall cure rate at that time), recruitment was terminated prematurely. CGP 56697 showed a superior 28-day cure rate (95.4% versus 19.7%; P < 0.001), time to parasite clearance (median = 36 versus 60 hr; P < 0.001), and resolution of fever (median = 18 versus 27 hr; P = 0.0456). This drug provides a safe, effective, and rapid therapy for the treatment of acute uncomplicated P. falciparum malaria.

Plasma nicotinic acid level in chloroquine treated rats.

The effect of chloroquine phosphate on plasma nicotinic acid levels in adult male albino rats was investigated. Pyrogen free chloroquine phosphate in physiological saline was administered subcutaneously to rats in a dose of 15 mg/kg body weight daily for eleven succeeding days in the treatment group. A control group was given equal volume of physiological saline daily for eleven succeeding days. Nicotinic acid concentration in the plasma was determined [1] Plasma nicotinic acid level was found to be significantly reduced (P < 0.01) throughout the duration of treatment. No change was observed in the control group. The significant reduction of plasma nicotinic acid level observed in this study may not be unrelated to competitive inhibition of the enzyme tryptophan dioxygenase by chloroquine phosphate.

Long-term application of disease modifying antirheumatic drugs (DMARD). A single-center, observational study of 1681 patients with rheumatoid arthritis (RA).

OBJECTIVE: To study the long-term efficacy and safety of methotrexate (MTX), intramuscular gold, azathioprine (AZA), chloroquine (CQ), sulphasalazine (SASP), and D-penicillamine (DPA) in rheumatoid arthritis (RA) patients. METHODS: Between 1979 and 1994, clinical data were prospectively gathered in a single center. 1681 patients were followed-up for at least 4 years. A 50% reduction of the swollen joint count was required to continue therapy. In addition, a modified Lansbury index, the Keitel function test, and laboratory parameters were determined every six months. Side effects leading to the discontinuation of treatment were recorded as well. RESULTS: After an observation period of more than four years, 39.6% and 28.3% of patients were taking MTX and AZA, respectively; 18.2% were receiving gold, 16.9% remained on DPA. SASP and CQ were still applied in 13.5% and 6.6%. MTX, AZA and SASP had a drop-out rate due to toxicity of 15.9%, 15.3% and 17.7%, whereas 34.8% had to discontinue CQ (gold: 27.4%, DPA: 26.9%). The majority of dropouts occurred within the first year of treatment. Subgroups of seropositive patients and patients with rheumatoid nodules had a poorer treatment efficacy irrespective of the DMARD. CONCLUSION: In the long-term application, MTX was the most efficient compound, followed by AZA, whereas CQ had the poorest drug survival. Our results underline the value of long-term observations under the conditions of clinical practice as a supplement to controlled clinical trials.

Electrophysiological effects of chilotoquine on tight junctions of immature rat Sertoli cells in vitro.

We investigated the effect of CQ, an antimalarial drug with antiprotease activity, and NH4Cl, a related amines on the development of intercellular tight junctions in cultured immature rat Sertoli cells. Sertoli cells were seeded in serum-free defined medium at a density of 3 x 10(6) cells/0.64 cm2/well on Matrigel-covered Millicell-HA filters. CQ (1 microM and 2 microM) or NH4Cl (6.25 mM and 12 mM) was added to the outer (basal) compartment of the bicameral system either on day 1 or day 7 of the culture. Formation of tight junctions was monitored by measurement of the transepithelial resistance (TER) at 24 hr intervals using an impedance meter. TER in untreated controls was 50 omega/cm2 on day 1, increased progressively to 80 omega/cm2 by day 7 and plateaued until day 12. The cells treated from day 1 with CQ showed dose-dependent progressive increase in TER until day 12, reaching 191 omega/cm2 in cells treated with 1 microM concentration. In cells treated with CQ starting from day 7 of culture onwards, TER patterns were similar to those noted following exposure to chloroquine from day 1. Also in cultures containing NH4Cl, in comparison to the control, the increase in TER was significantly higher. These observations demonstrate that CQ and HN4Cl promote tight junction formation between immature rat Sertoli cells invitro suggesting that antiproteases may be involved in the formation of blood-testis barrier.

Comparative efficacy of chloroquine plus chlorpheniramine and pyrimethamine/sulfadoxine in acute uncomplicated falciparum malaria in Nigerian children.

The efficacy of pyrimethamine/sulfadoxine (PS) and chloroquine plus chlorpheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was evaluated in 100 consecutive children with acute symptomatic uncomplicated falciparum malaria. Parasitaemia on day 3 following initiation of treatment, fever and symptom clearance times were significantly lower in the chloroquine/chlorpheniramine (CQ/CP) combination group than in the PS group. The cure rate was also significantly higher in the combination group. The combination cured all children who had failed PS treatment. Gametocytaemia and the gametocyte carrier rate following therapy were significantly lower in the combination group than in those receiving PS. Both treatments were well tolerated but adverse drug reactions were commoner in the children given PS. CQ/CP is effective in PS treatment failure in Nigerian children and may be useful for this condition in African children in general.

The use of formal and informal services for antenatal care and malaria treatment in rural Uganda.

The study aimed to analyze reasons for the use or non-use of antenatal care services and malaria treatment among pregnant women living in rural areas in Uganda. Focus group discussions with pregnant women, in-depth interviews with key informants (Traditional Birth Attendants (TBAs) and health workers) and a structured questionnaire administered to pregnant women were used to collect the relevant information. Antenatal care attendance was irregular and few women knew that the purpose of attending antenatal care was to monitor both the growth of the baby and the health status of the woman. Parity significantly influenced antenatal care attendance, but level of education, religion and marital status did not. Fifty-five per cent of the women stated that they had delivered outside the formal health delivery system despite antenatal care attendance. All women in their second pregnancy had delivered their first child in the village, despite TBA training to the contrary. Malaria as perceived by pregnant women is common and multiple health service providers are used for its treatment. About 66% of the mothers reported having suffered from malaria during the current pregnancy; of these more than half had received treatment outside the formal health delivery system. Self-treatment with drugs bought from ordinary shops was commonly reported. Nearly all women (93.3%) knew about the antimalarial drug chloroquine and 83% thought that it was used for the treatment of malaria, not for its prevention. Some women believed that the drug could cause abortion. Health seeking behaviour was influenced by several factors, including the perceived high cost of antenatal care services, of conducting a delivery and treatment, and perceived inadequacy of services provided by the formal health system. Inadequacy of formal health services was perceived by users to be partly due to understaffing and to irregular supply of essential drugs. Intensive health education to pregnant women on the safety of chloroquine use in pregnancy, the importance and the need for regular antenatal care attendance are recommended. In addition, training of more TBAs and continued educational efforts to upgrade their knowledge, regular and adequate supply of essential drugs, and free health services for high-risk groups such as pregnant women are recommended to improve antenatal care services and drug prophylaxis use in pregnancy.