Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial.

BACKGROUND: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. METHODS: An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months. RESULTS: Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults. CONCLUSIONS: PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. CLINICAL TRIALS REGISTRATION: NCT03129646.

Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis.

OBJECTIVES: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response. METHODS: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults. RESULTS: Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults. CONCLUSIONS: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.

Active circulation of varicella zoster virus among different age groups in Sudan.

In Sudan, data on varicella infections are lacking and the vaccine is currently not in use. The aim of this study was to investigate previous exposure to varicella zoster virus (VZV) among children and adults from the general population and among health-care workers (HCWs) in Khartoum. Dried blood spot samples collected between 2015 and 2016 from 294 children aged 1‒15 years, 153 adult volunteers and 241 HCWs were investigated for the presence of VZV IgG antibodies using ELISA. The overall seroprevalence of VZV IgG antibodies among the investigated cohorts was 50.4%, ranging between 14.3% in children and 79.3% in HCWs. Seropositivity increased with age among children and HCWs (P ⩽ 0.05). A relatively low seropositivity (64.7%) was observed among young adults and HCWs, suggesting that a high proportion of Sudanese adults remain susceptible. In hospital settings, this result implies a risk of nosocomial infection involving both HCWs and vulnerable patients. The results of this first VZV study in Sudan suggest active virus circulation in different age groups. Especially HCWs at the start of their career might benefit from vaccination, not only to save themselves from herpes zoster and its sequelae, but also to indirectly protect vulnerable patients.

Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6-180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.

Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa.

BACKGROUND: To expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes. METHODS: Data from 3 clinical trials were combined in this study, in which Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative polymerase chain reaction (qPCR) before, during, and up to 6 months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at 6 months. RESULTS: The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within 6 months of follow-up at a cutoff of 20 parasites/mL (area under the curve 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ = 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a > 80% power to detect a difference in cure rate between treatment regimens if this difference was high (> 50%) and when minimally 30 patients were included per regimen. CONCLUSIONS: Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.

Targets for protection and mitigation of radiation injury.

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.

Boosting immune system against cancer by resveratrol.

Modulation of the immune system is a critical part of anticancer therapies including immunotherapy, chemotherapy, and radiotherapy. The aim of immunomodulation in cancer therapy is boosting immune system cells including CD8+ T lymphocytes and natural killer (NK) cells, as well as suppression of immunosuppressive responses by macrophages and regulatory T cells (Tregs). Usually, using single or dual modality can induce immune system responses against cancer. However, immunosuppressive responses attenuate antitumor immunity following cancer therapy. Using some agents to boost immune system's function against cancer can increase therapeutic efficiency of anticancer therapy. Resveratrol, as a natural agent, has shown ability to modulate the immune system to potentiate antitumor immunity. Resveratrol has been shown to induce the release of anticancer cytokines such as IFN-γ and TNF-α and also inhibits the release of TGF-ß. It also can stimulate the polarization of CD4+ T cells and macrophages toward anticancer cells and reduce infiltration and polarization of immunosuppressive cells. Furthermore, resveratrol can sensitize cancer cells to the released dead signals by anticancer immune cells. This review explains how resveratrol can boost the immune system against cancer via modulation of immune cell responses within tumor.

Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa.

BACKGROUND: Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). METHODS: Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. RESULTS: A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. CONCLUSIONS: Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.

TGF-ß in radiotherapy: Mechanisms of tumor resistance and normal tissues injury.

Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-ß) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-ß is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-ß also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-ß triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-ß make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-ß and its consequences in both tumor and normal tissues.

NF-κB targeting for overcoming tumor resistance and normal tissues toxicity.

Radiotherapy and chemotherapy are two famous modalities in tumor-targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF-κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF-κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF-κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF-κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF-κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy.

Selenium as an adjuvant for modification of radiation response.

Ionizing radiation plays a central role in several medical and industrial purposes. In spite of the beneficial effects of ionizing radiation, there are some concerns related to accidental exposure that could pose a threat to the lives of exposed people. This issue is also very critical for triage of injured people in a possible terror event or nuclear disaster. The most common side effects of ionizing radiation are experienced in cancer patients who had undergone radiotherapy. For complete eradication of tumors, there is a need for high doses of ionizing radiation. However, these high doses lead to severe toxicities in adjacent organs. Management of normal tissue toxicity may be achieved via modulation of radiation responses in both normal and malignant cells. It has been suggested that treatment of patients with some adjuvant agents may be useful for amelioration of radiation toxicity or sensitization of tumor cells. However, there are always some concerns for possible severe toxicities and protection of tumor cells, which in turn affect radiotherapy outcomes. Selenium is a trace element in the body that has shown potent antioxidant and radioprotective effects for many years. Selenium can potently stimulate antioxidant defense of cells, especially via upregulation of glutathione (GSH) level and glutathione peroxidase activity. Some studies in recent years have shown that selenium is able to mitigate radiation toxicity when administered after exposure. These studies suggest that selenium may be a useful radiomitigator for an accidental radiation event. Molecular and cellular studies have revealed that selenium protects different normal cells against radiation, while it may sensitize tumor cells. These differential effects of selenium have also been revealed in some clinical studies. In the present study, we aimed to review the radiomitigative and radioprotective effects of selenium on normal cells/tissues, as well as its radiosensitive effect on cancer cells.

Radiation-Induced Heart Diseases: Protective Effects of Natural Products.

Cardiovascular diseases (CVDs) account for the majority of deaths worldwide. Radiation-induced heart diseases (RIHD) is one of the side effects following exposure to ionizing radiation (IR). Exposure could be from various forms such as diagnostic imaging, radiotherapy for cancer treatment, as well as nuclear disasters and nuclear accidents. RIHD is mostly observed after radiotherapy for thoracic malignancies, especially left breast cancer. RIHD may affect the supply of blood to heart muscles, leading to an increase in the risk of heart attacks to irradiated persons. Due to its dose-limiting consequence, RIHD has a negative effect on the therapeutic efficacy of radiotherapy. Several methods have been proposed for protection against RIHD. In this paper, we review the use of natural products, which have shown promising results for protection against RIHD.

Radioprotective Effect of Hesperidin: A Systematic Review.

Background and objectives: Ionizing radiation (IR) has been of immense benefit to man, especially for medical purposes (diagnostic imaging and radiotherapy). However, the risks of toxicity in healthy normal cells, leading to cellular damage as well as early and late side effects, have been major drawbacks. The aim of this study was to evaluate the radioprotective effect of hesperidin against IR-induced damage. Materials and Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were applied in reporting this study. A search was conducted using the electronic databases PubMed, Scopus, Embase, Google Scholar, and www.ClinicalTrials.gov for information about completed or ongoing clinical trials. Results: From our search results, 24 studies involving rats, mice, and cultured human and animal cells were included. An experimental case-control design was used in all studies. The studies showed that the administration of hesperidin reduced oxidative stress and inflammation in all investigated tissues. Furthermore, it increased 30-day and 60-day survival rates and protected against DNA damage. The best radioprotection was obtained when hesperidin was administered before irradiation. Conclusions: The results of the included studies support the antioxidant, anti-inflammatory, and antiapoptotic abilities of hesperidin as a potential radioprotective agent against IR-induced damage. We recommend future clinical trials for more insights.

Protective Effect of Melatonin Against Radiotherapy-Induced Small Intestinal Oxidative Stress: Biochemical Evaluation.

Background and Objectives: Radiation enteritis is a common side effect after radiotherapy for abdominal and pelvic malignancies. The aim of the present study was to investigate the protective effect of melatonin, known for its free radical scavenging ability, against radiotherapy-induced small intestinal oxidative damage. Materials and Methods: Thirty male Wistar rats were randomly assigned to six groups (5 rats in each) as follows: Group I (control group) rats received neither radiation nor melatonin; group II rats received only 8 Gy single dose of gamma radiation to their abdomen and pelvis regions; group III (administered with only 50 mg/kg melatonin); group IV (administered with only 100 mg/kg melatonin); group V (50 mg/kg melatonin + 8 Gy radiation), group VI (100 mg/kg melatonin + 8 Gy radiation). All rats were sacrificed after 5 days for biochemical assessments of their intestinal tissues. Results: Treatment with melatonin post irradiation significantly reduced malondialdehyde (MDA) levels as well as increased both superoxide dismutase (SOD) and catalase (CAT) activities of the irradiated intestinal tissues. In addition, melatonin administration with different doses pre irradiation led to protection of the tissues. Moreover, the 100 mg/kg dose was more effective compared to 50 mg/kg. Conclusions: The results of our study suggest that melatonin has a potent protective effect against radiotherapy-induced intestinal damage, by decreasing oxidative stress and increasing antioxidant enzymes. We recommend future clinical trials for more insights.

Genomic Instability and Carcinogenesis of Heavy Charged Particles Radiation: Clinical and Environmental Implications.

One of the uses of ionizing radiation is in cancer treatment. The use of heavy charged particles for treatment has been introduced in recent decades because of their priority for deposition of radiation energy in the tumor, via the Bragg peak phenomenon. In addition to medical implications, exposure to heavy charged particles is a crucial issue for environmental and space radiobiology. Ionizing radiation is one of the most powerful clastogenic and carcinogenic agents. Studies have shown that although both low and high linear energy transfer (LET) radiations are carcinogenic, their risks are different. Molecular studies have also shown that although heavy charged particles mainly induce DNA damage directly, they may be more potent inducer of endogenous generation of free radicals compared to the low LET gamma or X-rays. It seems that the severity of genotoxicity for non-irradiated bystander cells is potentiated as the quality of radiation increases. However, this is not true in all situations. Evidence suggests the involvement of some mechanisms such as upregulation of pro-oxidant enzymes and change in the methylation of DNA in the development of genomic instability and carcinogenesis. This review aimed to report important issues for genotoxicity of carcinogenic effects of heavy charged particles. Furthermore, we tried to explain some mechanisms that may be involved in cancer development following exposure to heavy charged particles.

Histopathological and Functional Evaluation of Radiation-Induced Sciatic Nerve Damage: Melatonin as Radioprotector.

Background and Objectives: Radiotherapy uses ionizing radiation for cancer treatment. One of the side effects of radiotherapy is peripheral neuropathy. After irradiation, the first stage of neuropathy involves electrophysiological, biochemical and histopathological variations, while the fibrosis of soft tissues surrounding the exposed nerve occurs in the second stage. The present study aimed to examine the radioprotective effects of melatonin against ionizing radiation-induced sciatic nerve damage. Materials and Methods: Sixty male Wistar rats were assigned to four groups: C (Control + Vehicle), M (Melatonin), R (Radiation + Vehicle), MR (Radiation + Melatonin). Their right legs were irradiated with a 30 Gy single dose of gamma rays. Then, 100 mg/kg melatonin was administered to the animals 30 min before irradiation once daily (5 mg/kg) until the day of rats' sacrifice. Their exposed nerve tissues were assessed using the sciatic functional index (SFI) and histological evaluation. Results: Four, 12 and 20 weeks post irradiation, the SFI results showed that irradiation led to partial loss of motor nerve function after 12 and 20 weeks. Histological evaluation showed the various stages of axonal degeneration and demyelination compared to the C and M groups. Scar-like tissues were detected around the irradiated nerves in the R group at 20 weeks, but were absent in the MR group. The SFI and histological results of the R group showed partial nerve lesion. However, in all cases, treatment with melatonin prevented these effects. Conclusions: Results showed that melatonin has the potential to improve functional and morphological features of exposed sciatic nerves. This could possibly improve the therapeutic window of radiotherapy.

Mitigation of Radiation-Induced Lung Pneumonitis and Fibrosis Using Metformin and Melatonin: A Histopathological Study.

Background and objectives: Pneumonitis and fibrosis are the most common consequences of lung exposure to a high dose of ionizing radiation during an accidental radiological or nuclear event, and may lead to death, after some months to years. So far, some anti-inflammatory and antioxidant agents have been used for mitigation of lung injury. In the present study, we aimed to detect possible mitigatory effects of melatonin and metformin on radiation-induced pneumonitis and lung fibrosis. Materials and methods: 40 male mice were divided into 4 groups (10 mice in each). For control group, mice did not receive radiation or drugs. In group 2, mice were irradiated to chest area with 18 Gy gamma rays. In groups 3 and 4, mice were first irradiated similar to group 2. After 24 h, treatment with melatonin as well as metformin began. Mice were sacrificed after 100 days for determination of mitigation of lung pneumonitis and fibrosis by melatonin or metformin. Results: Results showed that both melatonin and metformin are able to mitigate pneumonitis and fibrosis markers such as infiltration of inflammatory cells, edema, vascular and alveolar thickening, as well as collagen deposition. Conclusion: Melatonin and metformin may have some interesting properties for mitigation of radiation pneumonitis and fibrosis after an accidental radiation event.

Radiation-Induced Dual Oxidase Upregulation in Rat Heart Tissues: Protective Effect of Melatonin.

Background: Radiation-induced heart injury can lead to increased risk of heart failure, attack, and ischemia. Some studies proposed IL-4 and IL-13 as two important cytokines that are involved in late effects of ionizing radiation. On the other hand, these cytokines may, through upregulation of Duox1 and Duox2, induce chronic oxidative stress, inflammation, and fibrosis. In this study, we evaluated the upregulation of Duox1 and Duox2 pathways in hearts following chest irradiation in rats and then detected possible attenuation of them by melatonin. Materials and Methods: Twenty male Wistar rats were divided into four groups: (1) control; (2) melatonin treated (100 mg/kg); (3) radiation (15 Gy gamma rays); (4) melatonin treated before irradiation. All rats were sacrificed after 10 weeks and their heart tissues collected for real-time PCR (RT-PCR), ELISA detection of IL-4 and IL-13, as well as histopathological evaluation of macrophages and lymphocytes infiltration. Results: Results showed an upregulation of IL-4, IL4ra1, Duox1, and Duox2. The biggest changes were for IL4ra1 and Duox1. Treatment with melatonin before irradiation could attenuate the upregulation of all genes. Melatonin also caused a reduction in IL-4 as well as reverse infiltration of inflammatory cells. Conclusion: Duox1 and Duox2 may be involved in the late effects of radiation-induced heart injury. Also, via attenuation of these genes, melatonin can offer protection against the toxic effects of radiation on the heart.

Prevalence of high blood pressure in Iranian adults based on the 2017 ACC/AHA guideline.

Background: : In 2017, American College of Cardiology (ACC) and the American Heart Association (AHA) presented a new guideline for assessing blood pressure in adults. This study aimed to assess the prevalence of hypertension in Iranian adults based on ACC/AHA 2017 guideline. Methods: Data from 9801 Iranian adults (59.2% women) aged between 20-69 years were obtained from the sixth round of National Surveillance of Risk Factors of Non-Communicable Diseases (SuRFNCD) performed in 2011. Blood pressure was classified as normal, elevated blood pressure, and stage 1 and 2 hypertension using a weighted analysis and 2017 ACC/AHA guidelines. Data were presented as prevalence and 95% confidence interval (95% CI). All analyses were performed in Stata/SE 14.0. Results: Overall prevalence of hypertension in Iranian men was 52.0%. Also, 32.9% (95% CI: 29.9-36.0) and 19.1% (95% CI: 16.9-21.6) of men had stage 1 and 2 hypertension, respectively. In addition, 44.3% of women had hypertension, of whom 26.3% (95% CI: 24.5 - 28.2) had stage 1 and 18.0% (95% CI: 16.1-20.1) stage 2 hypertension. Furthermore, 16.5% (95% CI: 14.4-18.9) and 9.6% (95% CI: 7.86-11.7) of men and women had elevated blood pressure, respectively. Conclusion: The findings of this study indicated that adopting the 2017 ACC/AHA guidelines showed a higher prevalence of adult hypertension (48.2%) in Iran. In this study, the prevalence of hypertension in men was higher than in women, which was steadily increased by age in older adults in both sexes.

Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study.

BACKGROUND: Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. OBJECTIVES: To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. METHODS: Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. RESULTS: A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (-74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy). CONCLUSIONS: Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.