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Background: Healthcare costs are a major burden on the society of developing countries like India. Countries like India try to limit healthcare costs in support of generic medicine. So, the Indian government initiated the Jan Aushadhi scheme in 2008 to provide high-quality generic medication at a low cost. Aim: The aim of the study was to compare the cost difference between Jan Aushadhi generic pharmaceutical formulations and branded medications in Tamil Nadu. Settings and Design: Pharmaco economic - Cost minimization observational study. Methods and Material: Study Duration: Five months, from February 2023 to June 2023. Study Place: 10 Jan Aushadhi outlets from various districts of Tamil Nadu. Sampling technique: Convenience sampling technique Statistical analysis used: Mean median, mode and Percentage. Results: A total of 729 medications were available in 10 Jan Aushadhi outlets. The Jan Aushadhi outlet has the most cardiovascular medications and the fewest antimalarial medications among different categories of drugs. Erythropoietin has the biggest cost difference between the average cost of branded medications and Jan Aushadhi drug costs, while Digoxin has the lowest cost difference. Antitubercular drugs, Oxytocics, Antileprosy drugs, Antiparkinsonism categories of drugs also delisted in Jan Aushadhi outlet. Conclusions: Compared to branded drugs, Jan Aushadhi's generic drugs are 64.65 % less costly on an average as observed in our study. The manufacturer of Jan Aushadhi shops is a WHO and GMO-certified company, and they manufacture branded drugs. So, there will be no quality compromise in Jan Aushadhi's generic drugs. [ABSTRACT FROM AUTHOR]

Resistance to antileprosy drugs is one of the main contributors for the persistence of leprosy in the present era. In the absence of universal antimicrobial resistance (AMR) surveillance through the national program, the indications for resistance testing remain a important dilemma to clinicians. WHO recommendations mainly focus on clinical relapse, which could be picked up late with continued transmission and repeated leprosy reactions in the patient. We report here a series of eighteen leprosy cases who were tested for AMR in view of the positive morphological index after completion of multidrug therapy, chronic Erythema nodosum leprosum, and clinical relapse. [ABSTRACT FROM AUTHOR]

Lazarine leprosy is an unusual expression of usually borderline tuberculoid (BT) form characterized by spontaneous ulceration of skin lesions. This is presumably the result of an exaggerated type 1 reaction. It commonly occurs in the BT, borderline lepromatous forms and rarely in the lepromatous forms of leprosy. We report two cases of lazarine leprosy in the BT and BT downgrading to borderline lepromatous spectrum in healthy and immunocompetent males. [ABSTRACT FROM AUTHOR]

Background: Leprosy is a treatable disease; however, the release from treatment after completion of multidrug therapy (MDT) often does not equal absence of health problems. Consequently, sequelae interfere with the patient's perception of cure. The objective of this study was to analyze the factors associated with the perception of not being healed among people treated for leprosy in a highly endemic area in Brazil.Method: A cross-sectional study of perceived cure of leprosy in the post-release from treatment period was conducted in Cáceres in the state of Mato Grosso, Brazil. The study included a total of 390 leprosy patients treated with MDT and released after completion of treatment from 1 January 2000 to 31 December 2017. The dependent variable was self-reported cure of leprosy; the independent variables included clinical, operational and socioeconomic variables.Results: Out of the 390 former leprosy patients, 304 (77.9%) perceived themselves as cured and 86 (22.1%) considered themselves unhealed. Among the latter, 49 (57.0%) reported muscle weakness and joint pains. Individuals with complaints related to leprosy post-release from treatment had a 4.6 times higher chance to self-report as unhealed (OR 4.6; 95% CI 2.5-8.5). Patients with physical disabilities (PD) grade 1 and 2 at the time of the study had a 3.1 (OR 3.1; 95% CI 1.3-7.4) and 8.8 (OR 7.7; 95% CI 3.5-21.9) times higher likelihood to self-identify as unhealed, respectively.Conclusion: Among successfully treated leprosy patients, a quarter self-report as unhealed of the disease. The factors associated with the perception of being unhealed are PD and complaints related to leprosy in the post-release from treatment phase. [ABSTRACT FROM AUTHOR]

Several biologic agents have been approved for use in dermatology and other disciplines of medicine. However, based on the mechanism of action and a track record of the response, these agents are being increasingly used for off-label purposes to garner control of more remote and difficult disease processes. Herein, we present three difficult to treat patients where innovative uses of biologics beyond their approved indications have yielded good responses. Our first patient was a case of bullous pemphigoid, who showed excellent response to omalizumab. The second case was a patient of lepromatous leprosy with tenosynovitis and erythema nodosum leprosum, who was treated effectively with infliximab. Our third case was a treatment-resistant pyoderma gangrenosum, where infliximab showed a very good response. In the present study, we report the cases to highlight the usefulness of biologics that can expand much beyond the routine FDA approved indications. [ABSTRACT FROM AUTHOR]

Background: Thalidomide is the most teratogenic human medicine ever marketed and was associated with birth defects in approximately 10,000 children in the 1960s. The pharmacological effects of thalidomide are attributed to its anti-angiogenic, anti-inflammatory and modulatory effect on cytokines principally tumor necrosis factor-α, while the teratogenic effects are linked to two molecular targets, namely cereblon and tubulin. Teratogenicity is the gravest adverse effect of thalidomide depending on the dose and time of exposure. Nonetheless, with System for Thalidomide Education and Prescribing Safety program, the possibility of teratogenicity can be completely avoided. The sensitive period during pregnancy for thalidomide teratogenicity in humans is approximately 20-34 days after fertilization. Methods: Relevant articles were identified from Google scholar and PubMed (MEDLINE) using different search strategies. Conclusion: Clinical trials showed that thalidomide has been found effective in the treatment of advanced renal cancer, esophageal cancer, chemotherapy refractory endometrial cancer and pancreatic cancer, which can suggest its future therapeutic potential in cancer treatment. Thalidomide is also used in the treatment of inflammatory skin disorders and has shown promising effect in the treatment of autoimmune disorders and inflammatory bowel disease. Despite thalidomide being a renowned teratogen and neurotoxin, it has been successfully repositioned and FDA approved for the treatment of erythema nodosum leprosum and multiple myeloma under strict control. [ABSTRACT FROM AUTHOR]

Background: Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti.Methods: Mice with severe combined immunodeficiency were infected with 107B. microti-infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally.Results: Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites.Conclusions: Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis. [ABSTRACT FROM AUTHOR]

New derivatives of the anti-inflammatory, leprostatic drug dapsone 4 are synthesized, characterized and biologically screened by the treating the drug dapsone with chloroacetyl chloride in the presence of base. Both amino groups are acylated to give compound 6. The symmetrical acylated product then treated with Phenol, N-Acetyl-p-aminophenol, p-Chlorophenol, m-Chlorophenol, o-Hydroxybezoic acid and m-Hydroxybezoic acid to give compounds 8(a-f). The antimicrobial activity was tested for the synthesized compounds; activates were good compared to the parent drug. All the new compounds have scanned for their biological activities toward gram ‒ve and gram +ve (M. tuberculosis, S. pneumoniae, E. coli and P. mirabilis) bacteria, the synthesized derivatives gave moderate to good activity toward both mentioned types of bacteria. [ABSTRACT FROM AUTHOR]

Background: Indirect financial costs and barriers to health-care access might contribute to leprosy treatment non-adherence. We estimated the association of the Brazilian conditional cash transfer programme, the Programa Bolsa Família (PBF), on leprosy treatment adherence and cure in patients in Brazil.Methods: In this quasi-experimental study, we linked baseline demographic and socioeconomic information for individuals who entered the 100 Million Brazilian Cohort between Jan 1, 2007, and Dec 31, 2014, with the PBF payroll database and the Information System for Notifiable Diseases, which includes nationwide leprosy registries. Individuals were eligible for inclusion if they had a household member older than 15 years and had not received PBF aid or been diagnosed with leprosy before entering the 100 Million Brazilian Cohort; they were excluded if they were partial receivers of PBF benefits, had missing data, or had a monthly per-capita income greater than BRL200 (US$50). Individuals who were PBF beneficiaries before leprosy diagnosis were matched to those who were not beneficiaries through propensity-score matching (1:1) with replacement on the basis of baseline covariates, including sex, age, race or ethnicity, education, work, income, place of residence, and household characteristics. We used logistic regression to assess the average treatment effect on the treated of receipt of PBF benefits on leprosy treatment adherence (six or more multidrug therapy doses for paucibacillary cases or 12 or more doses for multibacillary cases) and cure in individuals of all ages. We stratified our analysis according to operational disease classification (paucibacillary or multibacillary). We also did a subgroup analysis of paediatric leprosy restricted to children aged up to 15 years.Findings: We included 11 456 new leprosy cases, of whom 8750 (76·3%) had received PBF before diagnosis and 2706 (23·6%) had not. Overall, 9508 (83·0%) patients adhered to treatment and 10 077 (88·0%) were cured. After propensity score matching, receiving PBF before diagnosis was associated with adherence to treatment (OR 1·22, 95% CI 1·01-1·48) and cure (1·26, 1·01-1·58). PBF receipt did not significantly improve treatment adherence (1·37, 0·98-1·91) or cure (1·12, 0·75-1·67) in patients with paucibacillary leprosy. For patients with multibacillary disease, PBF beneficiaries had better treatment adherence (1·37, 1·08-1·74) and cure (1·43, 1·09-1·90) than non-beneficiaries. In the propensity score-matched analysis in 2654 children younger than 15 years with leprosy, PBF exposure was not associated with leprosy treatment adherence (1·55, 0·89-2·68) or cure (1·57, 0·83-2·97).Interpretation: Our results suggest that being a beneficiary of the PBF, which facilitates cash transfers and improved access to health care, is associated with greater leprosy multidrug therapy adherence and cure in multibacillary cases. These results are especially relevant for patients with multibacillary disease, who are treated for a longer period and have lower cure rates than those with paucibacillary disease.Funding: CONFAP/ESRC/MRC/BBSRC/CNPq/FAPDF-Doenças Negligenciadas, the UK Medical Research Council, the Wellcome Trust, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES). [ABSTRACT FROM AUTHOR]

A leprosy reaction resembling Sweet syndrome was first described in 1987. This cutaneous manifestation can be classified as the type 2 reaction which arises from antigen–antibody interaction. It can occur in patients with diagnosed or undiagnosed leprosy, and men with borderline leprosy tend to exhibit this type of reaction. Triggering factors may include WHO multibacillary treatment or prescription antibiotics. Several reports of this clinical phenomenon have been published, making physicians consider it as part of this spectrum of the disease. Treatment regime can include systemic steroids and thalidomide. [ABSTRACT FROM AUTHOR]

Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the 'mouse-foot-pad propagation method', with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro. One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study. [ABSTRACT FROM AUTHOR]

Lepromatous leprosy represents a cutaneous infection by the bacterium Mycobacterium leprae. Once considered a common, fatal disease, leprosy has become increasingly rare with modern, inexpensive antibiotics. Most healthcare workers will never encounter a case of leprosy due to the low prevalence of the disease. However, military physicians, through deployments and contact with foreign-born servicemembers, are one of the first lines of defense against this disease. With an unknown method of transmission and an insidiously slow replication, it can take years for the disease to fully manifest. There are multiple cutaneous manifestations associated with the infection that can mimic other infectious etiologies, stalling appropriate diagnosis and treatment. To determine which treatment course is recommended requires evaluation of disease dissemination and the level of host immune response. As the incidence of reported leprosy cases continues to decline, disease education on diagnosis and treatment is imperative to enhance early detection and intervention. Understanding the populations at risk for leprosy and its insidious presentation will aid the practitioner in minimizing disease burden for both U.S. servicemembers and our foreign partners. [ABSTRACT FROM AUTHOR]

The aim of this work was to assess the feasibility of drug nanosystems combination for oral therapy of multibacillary leprosy. The anti-leprotic drugs dapsone (DAP) and clofazimine (CLZ) were incorporated within polymeric nanosystems and studied per se and in combination. DAP was loaded in Eudragit L100 nanoparticles (NPs-DAP) while CLZ was loaded in (poly(lactic-co-glycolic acid) (NPs-CLZ). The nanosystems exhibited around 200 nm in size and a drug loading of 12% for each drug. In vitro cytotoxicity on intestinal Caco-2 cells revealed that after 8 h incubation, DAP alone and within NPs were not toxic up to 100 μg mL −1 , while CLZ per se was toxic, reducing cell viability to 30% at 50 μg mL −1 . Caco-2 exposed to the combination of NPs-DAP (100 μg mL −1 ) and NPs-CLZ (50 μg mL −1 ) exhibited 80% of viability. Caco-2 monolayer permeability assays revealed that DAP and CLZ in the nanosystems per se or in NPs-DAP/ NPs-CLZ combination crossed the intestinal barrier. No significant differences were observed between the single nanosystems or in combination with the apparent permeability values and the amount of permeated drug. Thus, the NPs-DAP/NPs-CLZ combination seems to be a promising platform to deliver both drugs in association, representing an important step towards the improvement of multibacillary leprosy therapy. [ABSTRACT FROM AUTHOR]

Background: : WHO MDT is the main drug regimen for treating leprosy and has been used for more than three decades. Many cases of relapse of leprosy have been reported, which points towards the emergence of drug resistance with the antileprotic drugs.Objectives: : To find the resistance with the antileprotic drugs by detecting the mutations in drug resistance determining region of the rpoB, folP1 and gyrA genes of Mycobacterium leprae.Methods: Leprosy patients with bacterial index ≥2 were included in the study. The slides were further processed to extract genomic DNA, and polymerase chain reactions were performed to amplify the drug resistance determining region (DRDR) of rpoB, folP1 and gyrA genes. The samples in which genes could be amplified were subjected to DNA sequencing to detect mutations.Results: Out of 78 samples rpoB gene was amplified in 39 (50%), folP1 in 32 (41%) and gyrA in 45 (57.7%). In 20 (25.6%) samples no gene was amplified. Only 32 samples of rpoB, 25 samples of folP1 and 38 samples of gyrA gene were included in the study, rest were excluded due to sequencing error. No mutation was seen in rpoB gene and in folP1 gene. In gyrA gene samples mutations were seen in 8 (21%) samples, and were present at codon 91 GCA → GTA (Alanine → Valine).Limitations: : Small sample size and less efficient method to detect resistance.Conclusion: Resistance is not a problem with conventional drugs in MDT. It is more common with quinolones. [ABSTRACT FROM AUTHOR]

Some cutaneous adverse drug reactions (CADRs) are severe life-threatening conditions due to multisystem involvements with a high morbidity and mortality rates ranging from 25 - 70% and require immediate medical care. But there are huge controversies regarding the management because large clinical trials are lacking. Most frequent discussion and division occur regarding the use of systemic corticosteroid as early intervention with corticosteroids controls inflammation. Corticosteroids are potent agents that target several intracellular processes to modify almost all components of inflammatory and immune responses but their impact on the long term disease course is not known. Controlled relapses of rash and hepatitis may occur as corticosteroids are tapered. A chronic HHV6 activation promoted by systemic steroids could explain these relapses. Second important issue is the use of antitubercular drugs (ATD) in case of CADR due to multidrug therapy of ATD. As both the tuberculosis and CADR are life threatening conditions and we can not spare treatment of tuberculosis for CADR, we should come to a conclusion which is not yet decided. In the same way the use of antileprotic MDT in CADR due to MDT raises a similar controversy. So, here we focus on those controversies and discuss the issues. [ABSTRACT FROM AUTHOR]

Background Dapsone (4,4′-diaminodiphenylsulfone) has been widely used for the treatment of infections such as leprosy. Dapsone hypersensitivity syndrome (DHS) is a major side effect, developing in 0.5–3.6% of patients treated with dapsone, and its mortality rate is ∼10%. Recently, human leukocyte antigen (HLA)-B*13:01 was identified as a marker of susceptibility to DHS. Objectives To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view. Methods First, we used homology modeling to derive the three-dimensional structures of HLA-B*13:01 (associated with DHS) and HLA-B*13:02 (not so associated despite strong sequence identity [99%] with HLA-B*13:01). Next, we used molecular docking, molecular dynamic simulations, and the molecular mechanics Poisson-Boltzman surface area method, to investigate the interactions of dapsone with HLA-B*13:01 and 13:02. Results We found a crucial structural difference between HLA-B*13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the α-domain of HLA-B*13:02 is replaced with the less bulky Ile95 in HLA-B*13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B*13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B*13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B*13:02 does not seem to possess a binding pocket suitable for binding dapsone. Finally, a binding free energy calculation combined with a molecular dynamics simulation and the molecular mechanics Poisson-Boltzman surface area method indicated that the binding affinity of dapsone for HLA-B*13:01 would be much greater than that for HLA-B*13:02. Conclusions Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B*13:01. This may change the self-peptides that bind to HLA-B*13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility. [ABSTRACT FROM AUTHOR]

Background: Leprosy has a wide range of clinical and socio-economic consequences. India, Indonesia and Nepal contribute significantly to the global leprosy burden. After integration, the health systems are pivotal in leprosy service delivery. The Leprosy Post Exposure Prophylaxis (LPEP) program is ongoing to investigate the feasibility of providing single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) to the contacts of leprosy cases in various health systems. We aim to compare national leprosy control programs, and adapted LPEP strategies in India, Nepal and Indonesia. The purpose is to establish a baseline of the health system's situation and document the subsequent adjustment of LPEP, which will provide the context for interpreting the LPEP results in future.Methods: The study followed the multiple-case study design with single units of analysis. The data collection methods were direct observation, in-depth interviews and desk review. The study was divided into two phases, i.e. review of national leprosy programs and description of the LPEP program. The comparative analysis was performed using the WHO health system frameworks (2007).Results: In all countries leprosy services including contact tracing is integrated into the health systems. The LPEP program is fully integrated into the established national leprosy programs, with SDR and increased documentation, which need major additions to standard procedures. PEP administration was widely perceived as well manageable, but the additional LPEP data collection was reported to increase workload in the first year.Conclusions: The findings of our study led to the recommendation that field-based leprosy research programs should keep health systems in focus. The national leprosy programs are diverse in terms of organizational hierarchy, human resource quantity and capacity. We conclude that PEP can be integrated into different health systems without major structural and personal changes, but provisions are necessary for the additional monitoring requirements. [ABSTRACT FROM AUTHOR]

Background: The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse.Methods: We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively.Results: The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug.Conclusions: Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation. [ABSTRACT FROM AUTHOR]

Background: Due to its chronic subclinical course and large spectrum of manifestations, leprosy often represents a diagnostic challenge. Even with proper anti-mycobacteria treatment, leprosy follow up remains challenging: almost half of leprosy patients may develop reaction episodes. Leprosy is an infrequent complication of solid organ transplant recipients. This case report illustrates the challenges in diagnosing and managing leprosy and its reactional states in a transplant recipient.Case Presentation: A 53-year-old man presented 34 months after a successful renal transplantation a borderline-tuberculoid leprosy with signs of mild type 1 upgrading reaction (T1R). Cutaneous manifestations were atypical, and diagnosis was only made when granulomatous neuritis was found in a cutaneous biopsy. He was successfully treated with the WHO recommended multidrug therapy (MDT: rifampicin, dapsone and clofazimine). However he developed a severe T1R immediately after completion of the MDT but no signs of allograft rejection. T1R results from flare-ups of the host T-helper-1 cell-mediated immune response against Mycobacterium leprae antigens in patients with immunologically unstable, borderline forms of leprosy and has been considered an inflammatory syndrome in many aspects similar to the immune reconstitution inflammatory syndromes (IRS). The T1R was successfully treated by increasing the prednisone dose without modifying the other immunosuppressive drugs used for preventing allograft rejection. Immunological study revealed that the patient had a profound depletion of both in situ and circulating regulatory T-cells and lack of expansion of the Tregs upon M. leprae stimulation compared to T1R leprosy patients without iatrogenic immunosuppression.Conclusions: Our case report highlights that leprosy, especially in the transplant setting, requires a high degree of clinical suspicion and the contribution of histopathology. It also suggests that the development of upgrading inflammatory syndromes such as T1R can occur despite the sustained immunosuppressors regimen for preventing graft rejection. Our hypothesis is that the well-known deleterious effects of these immunosuppressors on pathogen-induced regulatory T-cells contributed to the immunedysregulation and development T1R. [ABSTRACT FROM AUTHOR]

Objective: Assess efficacy and safety of once-daily topical dapsone gel, 7.5% compared with vehicle for treating acne vulgaris (acne). Design: A pooled analysis of data from two identically designed, randomized, double-blind, vehicle-controlled, multicenter, 12-week clinical trials. Setting: Study sites in the United States and Canada. Participants: overall, 4,340 patients were randomized 1:1 to dapsone and vehicle. Criteria included age 12 years or older with acne diagnosis, 20 to 50 facial inflammatory lesions (papules and pustules), 30 to 100 facial noninflammatory lesions (open and closed comedones), and acne grade of 3 (moderate) on the Global Acne Assessment Score scale. Measurements: Efficacy assessments included the Global Acne Assessment Score success rate (proportion of patients with Global Acne Assessment Score of 0 [none] or 1 [minimal]) and percentage change from baseline in inflammatory and noninflammatory lesions at Week 12. Results: Global Acne Assessment Score success rates were 29.8 percent and 21.1 percent for patients who received dapsone gel, 7.5% and vehicle, respectively (p<0.001). Patients receiving dapsone gel, 7.5% had greater percentage change in lesion counts than patients receiving vehicle (inflammatory lesions: -54.6% vs. -48.1%; p<0.001; -45.1 %; noninflammatory lesions: -39.4%; p<0.001). Most adverse events were mild to moderate in severity. Mean dermal tolerability scores for stinging/burning, dryness, scaling, and erythema were similarly low with dapsone gel, 7.5% and vehicle. Conclusion: Dapsone gel, 7.5%, with a 50-percent greater dapsone concentration than twice-daily dapsone gel, 5% formulation, is applied topically once daily for acne, is effective, safe, and well-tolerated over 12 weeks, and has local tolerability similar to that of vehicle. www.clinicaltrials.gov identifiers: NCT01974141 and NCT01974323. [ABSTRACT FROM AUTHOR]

Background and Purpose: Kv 1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca(2+) signalling in T cells by regulating the membrane potential and with it the driving force for Ca(2+) influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen-induced Ca(2+) oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting Kv 1.3 channels with high potency and selectivity.Experimental Approach: We used patch-clamp methodology to investigate clofazimine's mechanism of action in Kv 1.3 channels expressed in HEK293 cells.Key Results: Clofazimine blocked Kv 1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use-dependent open-channel block during long depolarizations, resulting in accelerated K(+) current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use-dependent and state-dependent in that they clearly required prior channel opening. The clofazimine-sensitive closed-deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C-type inactivated state significantly affected. Kv 1.3 channels carrying the H399T mutation and lacking C-type inactivation were insensitive to clofazimine block of the closed-deactivated state, but retained their susceptibility to open-channel block.Conclusions and Implications: Given the prominent role of Kv 1.3 in shaping Ca(2+) oscillations, the use-dependent and state-dependent block of Kv 1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which Kv 1.3-expressing T cells play a significant role. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses a case study of a patient with dapsone hypersensitivity syndrome.

A series of new 6-(4-carboxy-3-methyl-2-phenylquinolin-6-ylsulfonyl)-3-methyl-2-phenylquinoline-4-carboxylic acids were synthesised by a one-pot reaction of dapsone, α-ketobutyric acid, and aromatic aldehydes in the presence of CuBr2 as a catalyst. Operational simplicity, mild reaction conditions, and eco-friendly procedure make this novel protocol a promising alternative for the preparation of quinoline-4-caboxylic acid derivatives. The structures of the products were established by elemental analyses and spectroscopic data. The biological activity of the new sulfone dimers was evaluated as having the potential for use as anticancer agents. [ABSTRACT FROM AUTHOR]

Highlights: [•] Highly sensitive RP-HPLC method development and extraction procedure optimization. [•] Quantitation of clofazimine (CLF) in rat plasma and bone marrow cells. [•] Quantitation of CLF over the concentration range of 15.6–2000.0ng/mL. [•] Application of validated method in preclinical pharmacokinetic study. [•] Significant distribution in bone marrow may cause the clastogenic effect of CLF. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The genus Hydnocarpus (Flacourtiaceae) includes forty species that are spread across the globe. In the Indian System of Medicine, Hydnocarpus pentandrus (Buch.-Ham.) Oken. is primarily used for treating leprosy and other skin disorders. It is known as “Chaulmoogra” and is also used to treat other indications including constipation, inflammation, blood disorders, and worm infestations. Various species of Hydnocarpus are also used in traditional medicine in China, Thailand, Malaysia, and Myanmar for several skin disorders. To assess the therapeutic potential of species from the Hydnocarpus genus and to determine future avenues for research. Methods: All relevant scientific literature published up to the end of December 2013 was retrieved via a library and electronic search (SciFinder, PubMed, ScienceDirect, and Google Scholar). Manual searches of traditional books like to ancient classics, including Vaidya Yoga Ratnavali, Siddha Materia Medica, and contemporary references including The Ayurvedic Pharmacopoeia of India and The Ayurveda Formulary, were also performed. Results: Seed oil from species of the Hydnocarpus genus is used for medicinal purposes, predominantly for various skin disorders. This oil is reported to contain a characteristic class of compounds known as cyclopentenyl fatty acids. Furthermore, seeds of this genus are reported to contain triglycerides of fatty acids, sterols, flavonoids, and flavonolignans. Hydnocarpin, a flavonolignan, is reported to potentiate antimicrobial and anticancer activity. The extracts and compounds isolated from this plant show a wide spectrum of pharmacological properties, including antibacterial, antileprotic, antitubercular, antipsoriatic, antirheumatic, hypolipidemic, antidiabetic, anticancer, anti-inflammatory, and antioxidant activities. The antileprotic activity is postulated to be due to the cyclopentenyl fatty acids present in the seed oil. Conclusion: Flavonolignans have an interesting chemical motif, and hydnocarpin and its congeners should be investigated for their activities and the mechanism underlying these activities. Multi-drug-resistant microbes are on the increase, and the possible inhibitory effect of these compounds when used with current antimicrobials should also be evaluated. Furthermore, unique cyclopentenyl fatty acids should also be investigated to understand the exact mechanism of action underlying antileprotic activity. Additional in depth phytochemical investigations of seed oil and extracts are required to tap the true potential of species from the Hydnocarpus genus. [Copyright &y& Elsevier]

Poly (amide-amidic acid) (PAA) and 4, 4′-diaminodiphenylsulfone (DDS) with varying molar ratios were used as co-curing agents to cure diglycidyl ether of bisphenol-A (DGEBA). The curing process was investigated. The differences between PAA and the conventional curing agents are discussed relative to the curing behavior and mechanism when cured with DGEBA. It was found that a lower temperature was needed to cure DGEBA when PAA was used as co-curing agent with DDS. There was only one step during the curing process of DGEBA and PAA, compared with the conventional curing agents (two steps). The activation energy (E) of the curing process of DGEBA with the co-curing agents, computed using model free estimations, was lower than that with DDS and PAA individually. [ABSTRACT FROM PUBLISHER]

Abstract: Research on existing drugs often discovers novel mechanisms of their action and leads to the expansion of their therapeutic scope and subsequent remarketing. The Wnt signaling pathway is of the immediate therapeutic relevance, as it plays critical roles in cancer development and progression. However, drugs which disrupt this pathway are unavailable despite the high demand. Here we report an attempt to identify antagonists of the Wnt–FZD interaction among the library of the FDA-approved drugs. We performed an in silico screening which brought up several potential antagonists of the ligand-receptor interaction. 14 of these substances were tested using the TopFlash luciferase reporter assay and four of them identified as active and specific inhibitors of the Wnt3a-induced signaling. However, further analysis through GTP-binding and β-catenin stabilization assays showed that the compounds do not target the Wnt-FZD pair, but inhibit the signaling at downstream levels. We further describe the previously unknown inhibitory activity of an anti-leprosy drug clofazimine in the Wnt pathway and provide data demonstrating its efficiency in suppressing growth of Wnt-dependent triple-negative breast cancer cells. These data provide a basis for further investigations of the efficiency of clofazimine in treatment of Wnt-dependent cancers. [Copyright &y& Elsevier]

The article presents a case study of a 49-year-old man suffering from unilateral, nontender left eyelid swelling.

Dapsone is a commonly prescribed leprostatic agent for the treatment of patients with leprosy, malaria, and a variety of skin diseases. Methemoglobinemia, a potentially life threatening when the oxygen carrying capacity of blood in the body tissues is reduced, is a known adverse effect of dapsone use. We report a case of dapsone induced Methemoglobinemia observed in the Emergency Service of Hospital General, Centro Médico Nacional la Raza, in a patient with vitiligo treated with dapsone and taking this for purposes of attempting suicide. The pathophysiological mechanisms, diagnosis, and treatment of dapsone-induced methemoglobinemia will be discussed. [ABSTRACT FROM AUTHOR]

Three cases with single lesion of Alopecia mucinosa (follicular mucinosis) were treated with antileprosy treatment and showed rapid and complete resolution of the lesions with no recurrence on extended follow-up. Two children, a boy aged 14 years and a girl aged 12 years presented themselves, each, with a single hypopigmented, hypoesthetic patch on the face. Clinically leprosy was suspected, however, skin biopsy from both patients revealed follicular mucinosis as the only pathological finding, without any granulomas. Based on clinical suspicion both were started on multi drug therapy (MDT) for leprosy with complete resolution of the lesions. The third case, male, aged 22 years presented with a single erythematous, hypoesthetic plaque on the forehead.This lesion had been diagnosed as follicular mucinosis with folliculo-tropic mycosis fungoides, in the USA. He too responded completely within 3 months with rifampicin, ofloxacin, minocycline (ROM) treatment, which was given once monthly for a total of 6 months and remains free of disease since the past 1 year. Follicular mucinosis as the only pathology may be seen in facial lesions of clinically suspected leprosy in children and young adults. Based on histological findings these cannot be diagnosed as leprosy and will be considered as Alopecia mucinosa. These lesions, however, are always single and show rapid and complete response to antileprosy treatment. The authors suggest that in regions endemic for leprosy, such as India, single lesion Alopecia mucinosa on the face in children and young adults should be given antileprosy treatment. [ABSTRACT FROM AUTHOR]

Mycobacteria leprae(leprosy) and HIV coinfection are rare in Kenya. This is likely related to the low prevalence (1 per 10,000 of population) of leprosy. Because leprosy is no longer a public health challenge there is generally a low index of suspicion amongst clinicians for its diagnosis. Management of a HIV-1-leprosy-coinfected individual in a resource-constrained setting is challenging. Some of these challenges include difficulties in establishing a diagnosis of leprosy; the high pill burden of cotreatment with both antileprosy and antiretroviral drugs (ARVs); medications' side effects; drug interactions; scarcity of drug choices for both diseases. This challenge is more profound when managing a patient who requires second-line antiretroviral therapy (ART). We present an adult male patient coinfected with HIV and leprosy, who failed first-line antiretroviral therapy (ART) and required second-line treatment. Due to limited choices in antileprosy drugs available, the patient received monthly rifampicin and daily lopinavir- /ritonavir-based antileprosy and ART regimens, respectively. Six months into his cotreatment, he seemed to have adequate virological control. This case report highlights the challenges of managing such a patient. [ABSTRACT FROM AUTHOR]

Abstract: The electrochemical reduction reaction of ranitidine, an antileprotic drug, was studied in an aqueous potassium chloride buffer with a stationary glassy carbon electrode. Cyclic voltammetric studies showed a well-defined reduction peak in the potential range from 0.0 to −1.8 V at pH values ranging from 1.0 to 11.0. The reduction was irreversible and has exhibited a diffusion-controlled adsorption. Controlled potential coulometry revealed four electron reductions with a total charge consumption of 785 μC. A systematic study of the experimental parameters that affected the square wave stripping response was carried out, and the conditions were optimized. A calibration plot was derived for the determination of the compound. The best determination range was obtained between 0.033 and 3.33 mg/L ranitidine with a relative standard deviation (n = 10) of 3 ppt (0.3%). Analytical applicability of the method was verified by the determination of ranitidine in tablets, dosing of drugs, gene profiling, monitoring of biologically important metabolites and urine samples. Also these techniques could make easier many arduous procedures such as in-situ assessment of weapons or toxic substances, environment pollution and others. [Copyright &y& Elsevier]

Abstract: Arginine methylation is an epigenetic modification that receives increasing interest as it plays an important role in several diseases. This is especially true for hormone-dependent cancer, seeing that histone methylation by arginine methyltransferase I (PRMT1) is involved in the activation of sexual hormone receptors. Therefore, PRMT inhibitors are potential drugs and interesting tools for cell biology. A dapsone derivative called allantodapsone previously identified by our group served as a lead structure for inhibitor synthesis. Acylated derivatives of p-aminobenzenesulfonamides and the antilepra drug dapsone were identified as new inhibitors of PRMT1 by in vitro testing. The bis-chloroacetyl amide of dapsone selectively inhibited human PRMT1 in the low micromolar region and was selective for PRMT1 as compared to the arginine methyltransferase CARM1 and the lysine methyltransferase Set7/9. It showed anticancer activity on MCF7a and LNCaP cells and blocked androgen dependent transcription specifically in a reporter gene system. Likewise, a transcriptional block was also demonstrated in LNCaP cells using quantitative RT-PCR on the mRNA of androgen dependent genes. [Copyright &y& Elsevier]

Abstract: This study was designed to evaluate the antimycobacterial, anti-reverse transcriptase, radical scavenging and antitumor activities of the methanol extracts of the twigs and leaves of three plants of the genus Treculia, namely Treculia obovoidea, Treculia africana and Treculia acuminata. The DPPH radical scavenging assay was used for the antioxidant test while the crown gall tumor assay was used for antitumor evaluation. The INT colorimetry and microplate Alamar blue assay (MABA) were used for antimycobacterial investigations. The results of the antimycobacterial assays, showed that the leaf crude extract of the three Treculia species as well as that from the twigs of T. africana were able to prevent the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis. The lowest MIC value (19.53µg/ml) was recorded with extract of the leaves of T. africana on M. smegmatis, and those of T. africana and T. acuminata against M. tuberculosis. All studied extracts inhibited at various extents the anti-reverse transcriptase activity at 200µg/ml. The best IC50 values, 31.1µg/ml, 29.5µg/ml and 21.1µg/ml were recorded respectively with the extracts of the leaves of T. obovoidea, T. acuminata and T. africana. Results of the antioxidant activity indicate a dose-dependent ability of sample to scavenge the DPPH radical. The lowest IC50 values were obtained with extracts of the leaves of T. acuminata (56.3µg/ml) and T. obovoidea (55.9µg/ml). Pronounced tumor-reducing activity was observed with the extracts of the leaves of T. africana (89.67%), T. acuminata (92.16%), T. obovoidea (96.67%) and that of the twigs of T. acuminata (87.18%). The overall results provide evidence that plants of the genus Treculia might be potential sources of antitubercular, anti-HIV and antitumor compounds. [Copyright &y& Elsevier]

Chlorproguanil (CPG)–dapsone (DDS)−artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG−DDS alone or plus artesunate. Adult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG–DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post–first dose. The pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on Cmax or AUC(0–24), except the 90% confidence interval (CI) for AUC(0−24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0−24) by 6−17% and Cmax by 0−16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0−24) by 13−47% and Cmax by 8−45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0−∞) was 64.6, 151 and 400 ng·h/ml and Cmax 48.9, 106 and 224 ng/ml respectively; DHA AUC(0−∞) was 538, 1,445 and 3,837 ng·h/ml and Cmax 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0−t) by 16% and Cmax by 5% and for DHA by 39 and 21% respectively. Artesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG−DDS−artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG−DDS combination has been withdrawn from clinical use. [ABSTRACT FROM AUTHOR]

Background: Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisininbased combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients. Methods and Findings: The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (&#x--65;1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/ 379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL). Conclusions: Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa. Trial Registration ClinicalTrials.gov NCT00344006 [ABSTRACT FROM AUTHOR]

Dapsone has been the principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy. It is also widely used by dermatologists in varied skin conditions like dermatitis herpetiformis, bullous pemphigoid, Behcet's disease, lupus erythematous and a host of other skin diseases. Hence an attempt has been made to review the utilization and qualitative evaluation of dapsone over a period of 6 months in a tertiary care teaching hospital. The study consisted of 80 patients (54 leprosy and 26 non-leprosy patients), prescribed with dapsone 100 mg oral once daily. The prescribing patterns of dapsone in leprosy and other dermatological conditions (non-leprosy) were analyzed and the safety, efficacy and appropriateness of the doses prescribed were reviewed. The adverse drug reactions observed in the study population were type I Lepra reactions, gastrointestinal side effects (abdominal pain and anorexia), peripheral neuropathy, other nervous side effects (insomnia, headache and vertigo) and other adverse reactions (fever and tinnitus). Patient information leaflets were distributed to patients to educate on the appropriate use of dapsone. [ABSTRACT FROM AUTHOR]

Background: Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria. Methods: Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1:2:2:2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28. Results: 1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site. Conclusions: Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children. [ABSTRACT FROM AUTHOR]

Immune reconstitution inflammatory syndrome (IRIS) is an unusual inflammatory reaction due to infectious and non-infectious causes occurring in human Immunodeficiency virus (HIV)-infected patients. IRIS occurs after the initiation of antiretroviral therapy. There are no reports of type I lepra reaction due to IRIS in published literature from India. We report two cases of HIV-infected males who presented with borderline tuberculoid leprosy in type 1 reaction after the initiation of highly active antiretroviral treatment (HAART). Case 1 presented with multiple, tender, erythematous and hypoesthetic plaques on the trunk and extremities after 3 months of antiretroviral therapy. In case 2, type I lepra reaction was observed 2 months after the initiation of HAART. [ABSTRACT FROM AUTHOR]

Abstract: The influence of the sulfone drug, diamino diphenyl sulfone (DDS or dapsone) on the phase transitions and dynamics of the model membrane, dipalmitoyl phosphatidylethanolamine (DPPE)–water/buffer has been studied using DSC and (1H and 31P) NMR. These investigations were carried out with DPPE dispersion in both multilamellar vesicular (MLV) and unilamellar vesicular (ULV) forms for DDS/DPPE molar ratio, R, in the range 0–0.5. DSC results indicate that the mechanism by which DDS interacted with the DPPE membrane is independent of the morphological organization of the lipid bilayer and the solvent (water or buffer) used to form the dispersion. DDS affected both the thermotropic phase transitions and the molecular mobility of the DPPE membrane. Addition of increasing amounts of DDS to the DPPE dispersion, resulted in the lowering of the gel to liquid–crystalline phase transition temperature (T m) hence increased membrane fluidity. At all concentrations, the DDS is located close to the interfacial region of the DPPE bilayer but not in the acyl chain region. The interesting finding with MLV is that the gel phase of DPPE–water/buffer both in presence and absence of DDS, on prolonged equilibration at 25°C, transforms to a stable crystalline subgel phase(s). The DPPE–water system forms both crystalline subgel LLC (with transition temperature T LC < T m) and LHC (with transition temperature T HC ≥ T m) phases, while the DPPE–buffer system forms only subgel LLC phase. The presence of the drug seems to (i) increase the strength of the subgel LLC phase and (ii) decrease the strength of subgel LHC (for R <0.5) phase. However, the value of the transition temperatures T LC and T HC does not change significantly with increasing drug concentration. [Copyright &y& Elsevier]

Painful erythematous plaques and a pathognomonic, dense, dermal infiltrate of neutrophils characterize Sweet syndrome. Although numerous instances of this disease have been reported in children, only four have had an associated immunodeficiency to date. Sweet syndrome has been traditionally treated with systemic corticosteroids despite an unknown pathogenesis. Prior reports suggest that immunodeficient children with Sweet syndrome may have a persistent course and fail to respond to standard treatment. We describe a child with debilitating Sweet syndrome and a primary immunodeficiency whose symptoms were controlled with intravenous immunoglobulin and dapsone. [ABSTRACT FROM AUTHOR]

Data on 90 patients (55 adults and 35 children) with chronic idiopathic thrombocytopenic purpura (ITP) and a platelet count of <50 × 109/L treated with dapsone at a dose of 1–2 mg/kg/d are presented. A response was observed in 57 (63.3%) patients. The average time for response was 3.5 months (range 1–9) and the average duration of treatment with dapsone was 10.4 months (range 4–14). Overall response rates of 65.7% and 61.8% were observed in children and adults respectively. Side effects requiring discontinuation of therapy were observed in three (2%) patients. These results demonstrate that dapsone is an effective, inexpensive and well-tolerated treatment for chronic ITP, in both children and adults and could be considered for patients who fail steroid therapy. [ABSTRACT FROM AUTHOR]

Antibodies against primaquine, pyrimethamine, dapsone, tetracycline, and doxycycline were raised in chickens inoculated with each drug conjugated to a rabbit albumin carrier. Antibody titres against drug and carrier were highest during week 6 postinoculation. Affinity purified anti-primaquine antibodies did not recognise other drugs, but affinity purified anti-doxycycline and anti-tetracycline antibodies recognised both tetracycline and doxycycline in addition to primaquine. Primaquine was detected in urine from 6 to 12 hours after ingestion of therapeutic doses of the drug by anti- primaquine antibodies in a competitive ELISA. Affinity purified anti-primaquine antibodies detected primaquine in the cytoplasm and localised in organelles in monocytes that had been incubated with therapeutic concentrations of the drug. [ABSTRACT FROM AUTHOR]

The need to consider using dapsone in pregnant women for its antimalarial activity is becoming greater in areas where Plasmodium falciparum resistance to chloroquine and pyrimethamine-sulfadoxine is rapidly increasing. Dapsone in combination with other antimalarials might provide a valuable alternative for both treatment and prophylaxis. This review assesses the clinical pharmacology of dapsone and its adverse drug reactions in relation to haemolysis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, blood dyscrasias and methaemoglobinaemia. Studies are summarised reporting its use in leprosy, dermatological and other conditions, and malaria, in relation to maternal and infant outcomes. A total of 924 pregnancies were identified during which dapsone therapy was taken. Only limited data are available and this precludes a meaningful quantitative benefit-risk analysis. Mild degrees of haemolysis consistently occur with continued therapy, although adverse effects may be less likely with intermittent treatment, as most reported adverse effects have occurred with long-term use of dapsone. There are a number of gaps in knowledge where more data are needed. These include no data on pharmacokinetics in pregnancy and whether these are altered with co-administration of chlorproguanil. Potential complications in women with severe anaemia are unknown and there is no information on haemolytic effects in women or the fetus with G6PD deficiency. The use of dapsone in HIV-infected women in malarious areas could carry increased risks because of the immunosuppressive actions of the drug. Trials of dapsone therapy in pregnancy should be considered in malarious areas where there is good reason for its deployment. Controlled trials have provided data on maternal tolerance, and dapsone in combination with other antimalarial drugs can offer clear benefit in terms of improved birthweight. The use of dapsone combinations should be considered when no good alternative is available and the threat of malaria is the greater risk. [ABSTRACT FROM AUTHOR]

Recent studies indicate that abnormalities of the interleukin-3 receptor (IL-3R) are frequently observed in acute myeloid leukemias (AMLs) and may contribute to the proliferative advantage of leukemic blasts. This review analyzes the evidences indicating that the IL-3R represents one of the target molecules involved in the stimulation of proliferation of AMLs, and the overexpression of the IL-3Ra chain may represent one of the mechanisms contributing to the development of a highly malignant leukemic phenotype. Furthermore, there is evidence that the IL-3Ra is a marker of leukemic stem cells, at variance with normal stem cells that are IL-3Ra-. Finally, the IL-3R may represent an important target for the development of new antileukemic drugs.Leukemia (2004) 18, 219-226. doi:10.1038/sj.leu.2403224 Published online 4 December 2003 [ABSTRACT FROM AUTHOR]