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The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis. In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells. HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 μM, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 μM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies. These results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.

Objective We aimed to investigate the efficacy and safety of a regimen combining bedaquiline and clofazimine in the treatment of refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC) or Mycobacterium abscessus subsp. abscessus (here Mab). Methods In this open-label, prospective pilot study, patients with refractory non-tuberculous mycobacterial pulmonary disease (NTM-PD) were enrolled to receive a regimen of bedaquiline and clofazimine alongside individualized background therapies. No control group was established in the study. Sputum samples were collected for culture at baseline (prior to treatment initiation) and then monthly thereafter. After the initial 6-month period, sputum collection frequency was reduced to every two months until trial completion. The primary end-point was sputum culture conversion rate. However, due to insufficient patient enrollment, we present these findings as a case series. Results A total of 11 patients were enrolled in this study, including 8 cases infected with Mycobacterium abscessus subsp. abscessus , 2 with Mycobacterium avium , and 1 with Mycobacterium intracellulare . Nine patients were resistant to clarithromycin. All 11 patients completed 18 months of follow-up. After 6 months of treatment, 45% (5/11) patients achieved culture conversion. However, after 18 months’ treatment, only 27% (3/11) maintained culture conversion. Chest CT imaging showed improvement in 5 patients, stability in 4 patients, and progression of lesions in 2 patients. The longest duration of bedaquiline use was 20 months. QTc interval prolongation was observed in 64% (7/11) of patients within 24 weeks, leading to permanent discontinuation of bedaquiline in one patient. The minimum inhibitory concentration (MIC) of bedaquiline ranged from ≤ 0.06 to 0.25 µg/mL prior to treatment, and two patients experienced an increase in MIC from ≤ 0.06 µg/mL to 0.12 µg/mL after treatment. The MICs of clofazimine were between 0.06 and 1 µg/mL. Conclusion The combination of bedaquiline and clofazimine may offer some clinical benefit in selected cases of advanced Mab and MAC lung diseases, but larger controlled studies are needed to confirm these preliminary findings. Trial registration This clinical study (ChiCTR2000037403) was registered on the ‌Chinese Clinical Trial Registry‌ website ( http://www.chictr.org.cn ) on ‌August 28, 2020‌.

In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

A young male in his late 20s presented with brownish discolouration of the conjunctiva and periocular area of both eyes. He was diagnosed as a case of lepromatous leprosy with recurrent type II lepra reaction 4 years ago and was started on multidrug therapy-multi bacillary, which included clofazimine. The best-corrected visual acuity was 20/20 in both eyes. Examination revealed reddish-brown discolouration of the facial skin including the periorbital area and the eyelids, brownish discolouration of the conjunctiva with shiny sub-conjunctival deposits and multiple polychromatic refractile crystalline corneal deposits. Both eyes had clear lenses with normal fundus. On follow-up after 4 months of discontinuing clofazimine and again after 1 year, the deposits had decreased than previous visits, but they had not totally disappeared. Few studies documented similar ocular side effects of this drug. When diagnosing crystalline deposits in the cornea and conjunctiva, one should rule out clofazimine-induced crystalline keratopathy especially in a leprosy patient.

Objectives Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. We aimed to assess key considerations for the clinical and programmatic use of clofazimine (Cfz), a riminophenazine with antimycobacterial activity currently used to treat leprosy. Design Fixed and random effects meta-analysis of cohort studies and systematic review. Setting Electronic and manual searches were combined. Inclusion criteria Observational studies on treatment of multidrug-resistant and extremely drug-resistant tuberculosis with Cfz or a Cfz-containing regimen, and published guidance and documents relating to cost and availability were eligible. Results 5 observational studies enrolled 861 patients, of which 602 received Cfz. The pooled proportion of adverse drug reactions requiring discontinuation of Cfz treatment was 0.1% (95% CI (0.0 to 0.6%)), and the median frequency of all adverse events was 5.1%. Cfz showed in vitro efficacy against Mycobacterium tuberculosis, and Cfz-containing regimens may have had a useful role in the treatment of patients with drug-resistant strains and who had limited alternative treatment options. However, Cfz uptake remains insufficient to meet global needs; there is only one internationally quality-assured manufacturer, which produces a limited quantity of the drug prioritised for treatment of leprosy, the only indication for which the drug is registered. Conclusions While the data were limited, Cfz was associated with a risk for adverse drug reactions comparable to that of first-line TB treatment, which could be reasonably managed under programmatic conditions. However, low market availability and high cost are important barriers to access to Cfz for patients with MDR-TB.

Background Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6–18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo , in HIV-infected patients with cryptosporidial diarrhea are not known. Methods CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose. Discussion This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6–18 months of age. Trial registration ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.

Clofazimine-induced crystal-storing histiocytosis is a rare but well-recognized condition reported in literature. In addition to common reddish discoloration of the skin, clofazimine produces gastrointestinal disorder, sometimes severe abdominal pain. Also, the pathologic and radiologic findings can produce diagnostic difficulties if the pathological changes caused by it are not known. The authors report a case in a patient of leprosy to emphasize the importance of history, radiologic, and pathologic findings in small intestine. Clofazimine crystals are red in the frozen section and display bright-red birefringence. With the knowledge of this rare condition caused by clofazimine, appropriate management to avoid an unnecessary laparotomy is possible.

A 30-year-old woman, case of lepromatous leprosy with recurrent type II lepra reaction, on tablet clofazimine 100 mg/ day was referred to us from dermatology clinic for brownish discoloration of conjunctiva. Careful literature search revealed that only one such case is reported by Font et al., [5] having estimated cumulative dose of clofazimine of 219 gm as compared to 891 gm in our patient In the case reported by Font et al., ultrastructural study of conjunctival biopsy demonstrated that many of fibroblasts and macrophages contained rectangular or rhomboidal empty spaces corresponding to crystals, which ranged from 1.5 to 7 x m in length.