Mortality Rates in Femoral Neck Fractures Treated With Arthroplasty in South Africa.

Objectives: To investigate the mortality rate for neck of femur fractures treated with arthroplasty at a tertiary level unit in South Africa and to evaluate the effect of known risk factors for mortality in neck of femur fractures treated with arthroplasty in the South African context. Design: Retrospective cohort study. The main outcome was to determine mortality rates during in hospital stay, at 3 months, 6 months 1 year post surgery. The secondary outcome was to determine factors influencing mortality at 30 days, 6 months and 12 months post-surgery. Results: Mortality rate was 3.3% in hospital, 5.6% at 30 days and 26.7% at 1 year. Age >79, ASA score >3, and cementing of the femur had statistically increased mortality risk (P < .001). Average length of hospital stay was 12.3 ± 5.1 days (range 3.0-41.0 days) with 73% of patients discharged back to pre-hospital home. Conclusion: Mortality rates after femur neck fracture arthroplasty in South Africa are slightly higher at 1 year compared to international data. However, the rates are comparably low during hospital stay, 30 day and at 6 months post-surgical intervals.

Global profile of individuals undergoing total knee replacement through the PROGRESS-PLUS equity lens: Protocol for a systematic review.

Background: Osteoarthritis (OA) is a heterogenous degenerative disorder often causing destructive joint changes with severe pain and functional disability. Modifiable and non-modifiable risk factors, social context and psychological factors influence the development and progression of the disease. Total knee replacement (TKR) aims at reducing pain and improving function and is more successful with pre-operative and post-operative rehabilitation. However, most international research on rehabilitation interventions is conducted in high income contexts. Objective: The aim of our systematic review is to gain an overview of the demographic and social profiles of adults undergoing TKR for primary knee OA in lower, middle- and high-income countries through a health equity lens to inform the translation of intervention research in local contexts. Methods: A systematic review will be conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligibility criteria include observational studies and grey literature (theses) since the beginning of the databases reporting on demographic data of adults awaiting or undergoing TKR surgery. The PROGRESS-Plus framework will be used to describe equity elements. Results: A narrative summary and description of the global profile of individuals undergoing total knee replacement for osteoarthritis. Conclusion: A snapshot of the global demographic and social profile of individuals receiving TKR for primary knee OA through an equity lens will shed light on the similarities and differences between individuals from different contexts. Global demographic profile information may inform or assist in the development of translational strategies for evidence-based rehabilitation. Clinical implications: Translation of existing rehabilitation interventions to local contexts could improve pre-operative and post-operative outcomes for individuals on our surgical waiting lists.

Prevalence of Sarcopenia in Older South African Patients Following Surgery for Fragility Fractures of the Hip.

INTRODUCTION: Geriatric patients with a fragility fracture of the hip (FFH) are especially prone to sarcopenia with poor functional outcomes and quality of life. We assessed the prevalence of sarcopenia in older South African patients with FFH. Risk factors for sarcopenia were also investigated. MATERIALS AND METHODS: From August 1 to November 30, 2018, all older patients with FFH were invited to participate. Sarcopenia was diagnosed based on the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Handgrip strength (HGS) and muscle strength were assessed. Muscle quantity was determined by dual-energy X-ray absorptiometry. Demographic information was collected, and 25-hydroxyvitamin D (25[OH]D) status was determined. RESULTS: Of the 100 hip fracture cases, 65 were enrolled, and 52% (34/65) were sarcopenic (women: 62%; men: 38%). HGS accurately identified sarcopenia (sensitivity and specificity: 100%). Patients >80 years of age had a prevalence of sarcopenia twice (18/21 [83%]) that of younger patients (18/44 [36%]). Women with sarcopenia were smaller than those without (weight: p < 0.001; height: p < 0.001; body mass index: p = 0.018). Low 25(OH)D was almost universally present, with median 25(OH)D levels significantly lower in the patients with sarcopenia (27 nmol/L [interquartile range {IQR}: 20-39] vs. 40 nmol/L [IQR: 29-53]). Several risk factors, including advanced age; female sex; a smaller body size, especially among women; limited physical activity; and low 25(OH)D levels, were identified. DISCUSSION: The accuracy of HGS testing in this cohort underscores EWGSOP2's recommendation that muscle strength is key to sarcopenia. Further study and follow-up are required to determine the clinical relevance of sarcopenia among FFH patients. CONCLUSION: The prevalence of sarcopenia in our FFH population is high. Sarcopenia is associated with poor patient outcomes following surgical intervention. Orthopaedic surgeons should therefore be cognizant of the presentation and associated risk of sarcopenia as our patient populations age.

QTc prolongation, increased NT-proBNP and pre-clinical myocardial wall remodeling in excessive alcohol consumers: The SABPA study.

Alcohol contributes greatly to vascular and structural modifications. Due to differences in the metabolism and tolerance of alcohol between ethnic groups, the manner of these modifications may differ. We investigated the association between alcohol consumption - measured via ethnic-specific gamma glutamyl transferase (γ-GT) cut-points - and markers of cardiac perfusion, electrical activity, and pre-clinical structural alterations. A South African target population study was performed in a bi-ethnic cohort (n = 405). Alcohol consumption was determined according to previously defined ethnic-specific γ-GT cut-points, where γ-GT ≥ 19.5 U/L and γ-GT ≥ 55 U/L indicated excessive alcohol consumption in Caucasians and Africans, respectively. Ambulatory 24-h blood pressure and electrocardiograms (ECG), 10-lead ECG left ventricular hypertrophy (LVH), ischemic events, N-terminal pro-brain natriuretic peptide (NT-proBNP), and QTc prolongation were assessed. Fasting blood samples were obtained. A poorer cardio-metabolic profile and mean 24-h hypertensive and ECG-LVH values were evident in high γ-GT groups of both ethnicities, when compared to their low counterparts. The African high γ-GT group reported a higher intake of alcohol and presented significant increases in NT-proBNP (p < 0.001), QTc prolongation (p = 0.008), and ischemic events (p = 0.013). Regression analyses revealed associations between ECG-LVH and NT-proBNP, QTc prolongation, ischemic events, and SBP, in the African high γ-GT group exclusively. High alcohol consumers presented delayed electrical conduction in the heart accompanied by ECG-LVH, ischemic events, and increased vaso-responsiveness, predominantly in Africans. Ultimately, increased left ventricular distension on a pre-clinical level may elevate the risk for future cardiovascular events in this population.

Cortisol:brain-derived neurotrophic factor ratio associated with silent ischaemia in a black male cohort: the SA BPA study.

AIM: Emotional distress has been associated with cardiovascular disease (CVD) in Africans. Cortisol and brain-derived neurotrophic factor (BDNF), as markers of emotional distress, increase cardiometabolic risk. We therefore aimed to investigate associations between cardiometabolic risk markers and the cortisol-to-BDNF ratio (cortisol:BDNF). METHODS: A cross-sectional study included a bi-ethnic gender cohort (n = 406) aged 44.7 ± 9.52 years. Ambulatory blood pressure (ABPM), ECG, fasting serum cortisol and BDNF levels and cardiometabolic risk markers were obtained. RESULTS: Africans had increased incidence of hyperglycaemia and 24-hour silent ischaemic events, and elevated 24-hour blood pressure (BP) and cortisol:BDNF ratios compared to Caucasians. Forward stepwise linear regression analysis underscored a similar trend with associations between hyperglycaemia, 24-hour BP [Adj R2 0.21-0.29; ß 0.23 (0.1-0.4); p = 0.01], silent ischaemia [Adj R2 0.22; ß 0.40 (0.2-0.6); p < 0.01] and cortisol:BDNF levels in Africans, mostly in the men. CONCLUSION: Attenuated cortisol levels in this group may be indicative of emotional distress and if chronic, drive the cortisol:BDNF ratio to desensitise BDNF. Desensitised cortisol:BDNF may sustain cardiometabolic risk and induce neurodegeneration in African men via silent ischaemia. Compensatory increases in blood pressure to increase perfusion and maintain homeostasis may increase coronary artery disease risk.

The defense response and alcohol intake: A coronary artery disease risk? The SABPA Study.

The behavioral defense coping response (DefS) as a measure of coping with emotional stress may increase alcohol intake (gamma glutamyl transferase (γGT)), the risk for coronary artery disease (CAD) and insulin sensitivity (homeostasis model assessment, HOMA). We assessed associations between coping and cardiometabolic risk markers in a bi-ethnic cohort (N = 390) from South Africa. Ambulatory blood pressure (BP) and ECG, fasting blood and coping scores were obtained. Africans, and mostly when utilizing DefS, showed higher 24h BP, a low-grade inflammatory state, central obesity, increased HOMA [4.07 (3.66, 4.47)] and more ST events compared to their Caucasian counterparts. ROC γ-GT analyses predicting 24-h ambulatory hypertension showed a higher γ-GT cut-point in Africans (55.4 U/l) than in Caucasians (19.5 U/l). Odds ratios (ORs) of γ-GT cut-points predicting 24-h ambulatory hypertension was evident in DefS African men [OR: 7.37 (95% CI: 6.71-8.05), p = 0.003] and in DefS Caucasians, albeit at a lower γ-GT cut-point (19.5 U/l). Higher γ-GT cut-points in DefS Africans or Caucasians were not associated with HOMA > 3. DefS accompanied by alcohol abuse in taxing emotional situations, if no social support is forthcoming, underscores a profile of reduced coronary perfusion. It may enhance vasoconstriction of the coronary arteries, with compensatory increases in BP, and induce a risk for future coronary artery disease.

Fibrosis and coronary perfusion - a cardiovascular disease risk in an African male cohort: The SABPA study.

Low-grade inflammation has been correlated with risk factors of cardiovascular diseases (CVD). Whether the pro-inflammatory and thrombotic ratio (fibrosis) may contribute to CVD is not known. We therefore aimed to assess whether Cornell Product left ventricular hypertrophy (LVH) is associated with fibrosis and coronary perfusion (silent ischemia) in a bi-ethnic male cohort from South Africa. A cross sectional study was conducted including 165 African and Caucasian men between the ages of 20-65. Fasting blood samples were obtained to measure fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α). Ambulatory blood pressure, ECG and 12 lead ECG measures were obtained to determine silent ischemic events (ST events) and LVH, respectively. Africans revealed more silent ischemia, higher 24 h blood pressure, inflammatory, coagulation as well as fibrosis levels than Caucasians. In a low-grade inflammatory state (CRP > 3 mg/l), Africans revealed higher fibrosis (p ≤ 0.01) values, but lower IL-6 and TNF-α values than Caucasians. Linear regression analyses in several models demonstrated positive associations between silent ischemia and fibrosis [Adj. R(2) 0.23; ß 0.35 (95% CI 0.13, 0.58), p ≤ 0.01]. In a low-grade inflammatory state (CRP>3mg/l), fibrinogen predicted AV-block in African men [OR 3.38 (95% CI 2.24, 4.53); p = 0.04]. Low-grade inflammation may induce AV-block through mechanisms involving fibrosis and ischemia to increase the burden on the heart in African men.

The utility of Xpert MTB/RIF performed on bronchial washings obtained in patients with suspected pulmonary tuberculosis in a high prevalence setting.

BACKGROUND: Xpert MTB/RIF has been shown to have a superior sensitivity to microscopy for acid fast bacilli (AFB) in sputum and has been recommended as a standard first line investigation for pulmonary tuberculosis (PTB). Bronchoscopy is a valuable tool in diagnosing PTB in sputum negative patients. There is limited data on the utility of Xpert MTB/RIF performed on bronchial lavage specimens. Our aim was to evaluate the diagnostic efficiency of Xpert MTB/RIF performed on bronchial washings in sputum scarce/negative patients with suspected PTB. METHODS: All patients with a clinical and radiological suspicion of PTB who underwent bronchoscopy between January 2013 and April 2014 were included. The diagnostic efficiencies of Xpert MTB/RIF and microscopy for AFB were compared to culture for Mycobacterium tuberculosis. RESULTS: Thirty nine of 112 patients were diagnosed with culture-positive PTB. Xpert MTB/RIF was positive in 36/39 with a sensitivity of 92.3% (95% CI 78-98%) for PTB, which was superior to that of smear microscopy (41%; 95% CI 26.0-57.8%, p = 0.005). The specificities of Xpert MTB/RIF and smear microscopy were 87.7% (95% CI 77.4-93.9%) and 98.6% (95% CI 91.6%-99.9%) respectively. Xpert MTB/RIF had a positive predictive value of 80% (95% CI; 65-89.9%) and negative predictive value of 95.5% (95% CI 86.6-98.8%). 3/9 patients with Xpert MTB/RIF positive culture negative results were treated for PTB based on clinical and radiological findings. CONCLUSION: Xpert MTB/RIF has a higher sensitivity than smear microscopy and similar specificity for the immediate confirmation of PTB in specimens obtained by bronchial washing, and should be utilised in patients with a high suspicion of pulmonary tuberculosis.

Preclinical evaluation of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-ubiquicidin as a radioligand for PET infection imaging.

UNLABELLED: Antimicrobial peptides such as ubiquicidin (UBI) are believed to differentiate between mammalian and bacterial or fungal cells. (99m)Tc-UBI29-41 was previously tested for detecting infection in humans using SPECT. For the present study, the UBI fragment UBI29-41 (TGRAKRRMQYNRR) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA), radiolabeled with (68)Ga, and investigated in a rabbit infection model. METHODS: (68)Ga was obtained from a 1.85-GBq (68)Ge/(68)Ga generator. New Zealand White rabbits were anesthetized with ketamine/medetomidine before tracer administration and placed in a clinical PET/CT scanner. (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic-acid-ubiquicidin29-41 ((68)Ga-NOTA-UBI29-41) was formulated in saline solution, and 101 ± 41 MBq were administered intravenously. The tracer distribution was studied by PET/CT imaging in animals (a) that were healthy, (b) bearing muscular Staphylococcus aureus infections and turpentine oil-induced muscular inflammations, and (c) bearing ovalbumin-induced lung inflammations. Static PET/CT imaging was performed at different time intervals up to 120 min after injection. For calculation of target-to-nontarget ratios, standardized uptake values were normalized against healthy thigh muscle, representing nontargeted tissue. RESULTS: PET/CT images of healthy animals showed predominant distribution in the kidneys, liver, and bladder; heart and spleen showed moderate, declining uptake, only. The biologic half-life in blood was 29 min. Urinary accumulation of (68)Ga-NOTA-UBI29-41 peaked at 3.8 ± 0.91 percentage injected dose per gram (%ID) at 120 min, and 88 ± 5.2 %ID was recovered in total urine. (68)Ga-NOTA-UBI29-41 imaging in (b) selectively visualized the muscular infection site and was differentiated from sterile inflammatory processes. Standardized uptake value ratios for muscles (infected/inflamed) were 2.9 ± 0.93, 2.9 ± 0.50, 3.5 ± 0.86, and 3.8 ± 0.90 at 5, 30, 60, and 90 min after injection, respectively. Rabbit lungs with asthma showed insignificant uptake. CONCLUSION: (68)Ga-NOTA-UBI29-41 was strongly localized in bacteria-infected areas and minimally detected in a sterile inflammation area in rabbit muscles. The findings propose this compound to be an excellent first-line PET/CT tracer to allow the distinguishing of infection from inflammation.

Radiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand.

The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H(3) antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]1 in regions rich in H(3) receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [(11)C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [(11)C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.

A reassessment of argasid tick salivary gland ultrastructure from an immuno-cytochemical perspective.

Previous morphological and histochemical studies of argasid tick salivary glands indicated that they were less complex than ixodid salivary glands, with only three granular cell types. The present study shows that there exist at least four different granular cell types in the salivary glands of the argasid tick Ornithodoros savignyi, based on immuno-localization of the anti-hemostatic factors, apyrase and savignygrin. Both anti-hemostatic factors were localized to dense core granule type 'a' and to granule type 'b', that shares a similar homogenous morphology with non-labeled granule type 'd'. Furthermore, the major tick salivary gland proteins (TSGPs), previously implicated in granule biogenesis, were localized to all the granular cell types. This indicates that granular cell types with different morphologies can express the same proteins, while cell types that show similar morphologies may not express the same proteins. Argasid tick salivary glands seem to be more complex than previously thought and might not be amenable to morphological classification alone. Alternative classification methodologies that rely on physical expression patterns of the salivary gland proteome might be more reliable as markers for a specific granular cell type.

Synthesis and evaluation of radiolabeled analogs of the antidepressant drug zimelidine as potential SPECT-ligands for the serotonin transporter.

Z-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridinyl)-2-propen-1-amine or zimelidine (ZIM) and its first metabolite nor-zimelidine, were radioiodinated via a nonisotopic exchange, using the Cu(I)-assisted nucleophilic labeling method. To evaluate their potential as SPECT ligands for the serotonin transporter (SERT), the biodistribution of both ligands was determined and pretreatment "blocking" studies performed. Both radioligands demonstrated a good brain penetration of 0.8-1% ID/g, stable after 60 min., p.i., and a brain/blood ratio of up to 3. In vivo brain distribution did not reveal specific binding. Blocking studies by pretreatment with a known SERT ligand, had minor influence on the uptake of [(123)I]I-ZIM, between the several isolated brain regions. It may therefore be concluded that [(123)I]I-ZIM and [(123)I]I-nor-ZIM do not appear to be promising SPECT ligands for the SERT.

Pathogenic mechanisms of sand tampan toxicoses induced by the tick, Ornithodoros savignyi.

The tick, Ornithodoros savignyi has been implicated in inducing paralysis and tampan toxicosis. In this study, a basic toxin (TSGP4) was identified and the presence of an acidic toxin (TSGP2) was confirmed. Both basic and acidic toxins were more lethal than previously described, with TSGP4 (34microg) and TSGP2 (24microg) causing mortality of adult mice within 30min. Pathological effects on the cardiac system, notably of salivary gland extract on an isolated rat heart perfusion system and of purified toxins on mouse electrocardiogram patterns could be observed. TSGP4 caused Mobitz type ventricular block, while TSGP2 induced ventricular tachycardia. Conversely, fractions from reversed phase high performance liquid chromatography preparations caused paralysis-like symptoms of the limbs after only 48h. The toxins also differ from previously described tick paralysis toxins in terms of molecular behavior and properties. These results indicate that tampan toxicoses and tick paralysis are unrelated pathogenic phenomena.

Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials.

A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virus-infected children.

Although dapsone is a commonly used alternative agent for prophylaxis against Pneumocystis carinii pneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0. 3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h; P = 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age.

The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug.

We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L, respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is reduced 10-12-fold by 10(-5) mol/L of FA, and virtually eliminated by 10(-5) mol/L of FNA. Folates do not antagonise the action of WR99210 against Kenyan strains, and only partially antagonize the action of WR99210 action against the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no antagonism of the action of PS-15. The inability of folates to antagonize the action of WR99210 can be explained in terms of high drug-enzyme affinity, but this does not account for the inability of FA and FNA to antagonize PS-15. These results suggest that action of PS-15 against P. falciparum is primarily due to a non-folate mechanism.

Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. ACTG 179 Study Team. AIDS Clinical Trials Group.

BACKGROUND: Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. METHODS: Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. RESULTS: Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. CONCLUSION: Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.

Methaemoglobin formation due to nitrite, disulfiram, 4-aminophenol and monoacetyldapsone hydroxylamine in diabetic and non-diabetic human erythrocytes in vitro.

Nitrite, monoacetyl dapsone hydroxylamine, 4-aminophenol and disulfiram-mediated methaemoglobin formation was studied in human diabetic and non-diabetic erythrocytes in vitro. Diabetic intact erythrocytes were significantly less sensitive compared with those of non-diabetics to haemoglobin oxidation caused by the hydroxylamine, nitrite and 4-aminophenol, but not disulfiram. In haemolysates, differential sensitivity did occur with disulfiram and was partially retained with 4-aminophenol and nitrite. The differences were lost with 4-aminophenol, nitrite and disulfiram in the presence of haemoglobin purified from the respective erythrocyte types. Diethyl maleate reduced methaemoglobin formation in non-diabetic intact erythrocytes with 4-aminophenol, the hydroxylamine and disulfiram, but not with nitrite. Overall, the differential sensitivity to methaemoglobin formation seen in diabetic compared with non-diabetic erythrocytes, is probably linked to differences in the respective cells' cytosolic anti-oxidant systems.

Combination of PS-15, epiroprim, or pyrimethamine with dapsone in prophylaxis of Toxoplasma gondii and Pneumocystis carinii dual infection in a rat model.

In a rat model of dual infection, we studied such dihydrofolate reductase (DHFR) inhibitors as PS-15 (25 mg/kg of body weight), epiroprim (100 mg/kg), and pyrimethamine (3 mg/kg) alone or in combination with various doses of dapsone (50, 25, or 5 mg/kg) for the prevention of pneumocystosis and toxoplasmosis. Rats latently infected with Pneumocystis carinii were immunosuppressed by corticosteroids for 7 weeks, and the drugs were administered from the initiation of the corticosteroid treatment. At week 5, the rats were inoculated intraperitoneally with the RH strain of Toxoplasma gondii. Infections were monitored by the counting of P. carinii cysts in lung homogenates and the titration of T. gondii in organs by quantitative culture and an indirect immunofluorescence assay. Fourteen of the 15 untreated rats died after T. gondii challenge, with P. carinii infection in the lungs and T. gondii infection in the lungs, liver, spleen, and brain. Of the three tested DHFR inhibitors, only PS-15 exhibited anti-P. carinii activity; none prevented toxoplasmosis in 100% of the rats. After the DHFR inhibitors were combined with dapsone (50 or 25 mg/kg), both pneumocystosis and toxoplasmosis were completely prevented. On the basis of these results, PS-15 and epiroprim combined with dapsone are candidates for use for the prevention of both pneumocystosis and toxoplasmosis.