Isobolographic analysis of co-administration of two plant-derived antiplasmodial drug candidates, cryptolepine and xylopic acid, in Plasmodium berghei.

BACKGROUND: Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, cryptolepine and xylopic acid and the relationship that exists in their combined administration determined. METHODS: Anti-plasmodial effect of cryptolepine (CYP) (3, 10, 30 mg kg-1) and xylopic acid (XA) (3, 10, 30 mg kg-1) was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment. The respective doses which produced 50% chemosuppression (ED50) was determined by iterative fitting of the log-dose responses of both drugs. CYP and XA were then co-administered in a fixed dose combination of their ED50s (1:1) as well as different fractions of these combinations (1/2, 1/4, 1/8, 1/16 and 1/32) to find the experimental ED50 (Zexp). The nature of interaction between cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Zexp with the theoretical ED50 (Zadd). Additionally, the effect of cryptolepine/xylopic acid co-administration on vital organs associated with malarial parasiticidal action was assessed. RESULTS: The Zadd and Zexp were determined to be 12.75 ± 0.33 and 2.60 ± 0.41, respectively, with an interaction index of 0.2041. The Zexp was significantly (P < 0.001) below the additive isobole indicating that co-administration of cryptolepine and xylopic acid yielded a synergistic anti-plasmodial effect. This observed synergistic antiplasmodial effect did not have any significant deleterious effect on the kidney, liver and spleen. However, the testis were affected at high doses. CONCLUSION: The co-administration of cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity.

Unmasking the Risk Factors Associated with Undiagnosed Diabetes and Prediabetes in Ghana: Insights from Cardiometabolic Risk (CarMeR) Study-APTI Project.

INTRODUCTION: Undiagnosed diabetes poses significant public health challenges in Ghana. Numerous factors may influence the prevalence of undiagnosed diabetes among adults, and therefore, using a model that takes into account the intricate network of these relationships should be considered. Our goal was to evaluate fasting plasma levels, a critical indicator of diabetes, and the associated direct and indirect associated or protective factors. METHODS: This research employed a cross-sectional survey to sample 1200 adults aged 25-70 years who perceived themselves as healthy and had not been previously diagnosed with diabetes from 13 indigenous communities within the Cape Coast Metropolis, Ghana. Diabetes was diagnosed based on the American Diabetes Association (ADA) criteria for fasting plasma glucose, and lipid profiles were determined using Mindray equipment (August 2022, China). A stepwise WHO questionnaire was used to collect data on sociodemographic and lifestyle variables. We analyzed the associations among the exogenous, mediating, and endogenous variables using a generalized structural equation model (GSEM). RESULTS: Overall, the prevalence of prediabetes and diabetes in the Cape Coast Metropolis was found to be 14.2% and 3.84%, respectively. In the sex domain, females had a higher prevalence of prediabetes (15.33%) and diabetes (5.15%) than males (12.62% and 1.24%, respectively). Rural areas had the highest prevalence, followed by peri-urban areas, whereas urban areas had the lowest prevalence. In the GSEM results, we found that body mass index (BMI), triglycerides (TG), systolic blood pressure (SBP), gamma-glutamyl transferase (GGT), and female sex were direct predictive factors for prediabetes and diabetes, based on fasting plasma glucose (FPG) levels. Indirect factors influencing diabetes and prediabetes through waist circumference (WC) included childhood overweight status, family history, age 35-55 and 56-70, and moderate and high socioeconomic status. High density lipoprotein (HDL) cholesterol, childhood overweight, low physical activity, female sex, moderate and high socioeconomic status, and market trading were also associated with high BMI, indirectly influencing prediabetes and diabetes. Total cholesterol, increased TG levels, WC, age, low physical activity, and rural dwellers were identified as indirectly associated factors with prediabetes and diabetes through SBP. Religion, male sex, and alcohol consumption were identified as predictive factors for GGT, indirectly influencing prediabetes and diabetes. CONCLUSIONS: Diabetes in indigenous communities is directly influenced by blood lipid, BMI, SBP, and alcohol levels. Childhood obesity, physical inactivity, sex, socioeconomic status, and family history could indirectly influence diabetes development. These findings offer valuable insights for policymakers and health-sector stakeholders, enabling them to understand the factors associated with diabetes development and implement necessary public health interventions and personalized care strategies for prevention and management in Ghana.

Assessment of malaria diagnostic methods and treatments at a Ghanaian health facility.

INTRODUCTION: it has been more than a decade since the World Health Organization (WHO) recommended parasitological confirmation of malaria before treatment begins. Light microscopy and rapid diagnostic tests are currently being used for diagnosing malaria in routine clinical care settings. Many clinicians have however raised questions about the competencies of laboratory staff who perform these tests and the performance of these diagnostic methods. This study aimed at assessing the performance of microscopy and two rapid diagnostic test kits in the hands of routine laboratory staff compared to expert microscopy as well as assess the performance of clinical diagnosis. METHODS: this was a cross sectional study involving 799 participants of all ages who visited the out patient department of the University of Cape Coast Hospital with symptoms suggestive of malaria. RESULTS: when the different methods were compared to expert microscopy, the rapid diagnostic test kits had the highest sensitivities, Wondfo 94.83% (95% CI: 85.62-98.20) and CareStart 91.38 (95% CI: 81.02-97.14). Microscopy by laboratory staff had a sensitivity of 68.79 (95% CI: 55.46-80.46) whilst clinical diagnosis had the lowest sensitivity of 17.24 (95% CI: 8.59-29.43). Cohen´s kappa coefficient was used to measure the level of agreement of the methods with expert microscopy. Microscopy by laboratory staff, CareStart and Wondfo showed substantial measures of agreement (k = 0.737, 0.683, and 0.691 respectively). CONCLUSION: these findings suggest that clinical diagnosis is highly unreliable whilst rapid diagnostic tests and microscopy performed by routine laboratory staff could be trusted by clinicians as reliable diagnostic methods.

Assessment of the knowledge, attitude and practices of prescribers regarding malaria diagnosis: a cross sectional study among Ghanaian prescribers.

INTRODUCTION: Malaria has proven to be the most fatal parasitic disease known to man. Among the pillars to malaria control are early and accurate diagnosis. In 2010, the World Health Organization launched its test, treat and track initiative which seeks to ensure that all suspected cases of malaria are tested. However, after several years of implementation, the use of malaria tests in diagnosing malaria has not been optimum. This study was conducted to assess the level of knowledge of prescribers on malaria Rapid Diagnostic Test and microscopy and to determine factors influencing prescribers' decision to request and use malaria tests in practice. METHODS: A cross sectional study was carried out among 100 prescribers of various categories working in 4 hospitals in Ghana in March 2019. A pre-tested self-administered questionnaire was used to collect information on knowledge, malaria diagnostic practices and challenges faced by prescribers regarding parasitological testing for malaria in their health facilities. RESULTS: Overall, 73% of respondents had good knowledge on malaria diagnostics. Routine use of malaria tests in diagnosing malaria was reported as 84%. Only 9% reported complete reliance on test results. Most participants (90%) reported awareness of the test-based case management of malaria. CONCLUSION: This study demonstrated that even though there was a high level of awareness of the test-before treatment policy among prescribers, significant numbers did not routinely request a malaria test for all suspected cases of malaria. Factors cited as barriers by prescribers were both health worker and health-system related that are all potentially modifiable.

Evaluation of urinalysis parameters and antimicrobial susceptibility of uropathogens among out-patients at University of Cape Coast Hospital.

BACKGROUND: Urinary tract infection (UTI) is a major global public health issue. The gold standard for diagnosing UTI is urine culture. This is however labour intensive and time consuming. Many prescribers therefore rely on urinalysis in diagnosing UTI. This study sought to evaluate the performance of some parameters of urinalysis as predictors of urine culture positivity. The common causative agents and their antibiotic susceptibility patterns were also determined. METHODS: A cross sectional study was carried out at the University of Cape Coast Hospital from July 2017 - December 2017 among out-patients. The performance characteristics of leukocyte esterase (3+) and nitrite reactions were estimated and compared with urine culture. Antimicrobial susceptibility tests were done using disc diffusion technique described by Kirby-Bauer. RESULTS: Prevalence of UTI in this study was 30.0% (64/213). The most prevalent pathogen was E. coli (20, 31.2%), followed by S. saprophyticus (9, 14.1%). Most of the bacteria (52, 94.5%) were sensitive to amikacin, followed by ciprofloxacin (42, 76.3%). The most sensitive (94.4%) of the parameters was pus cells [>5 white blood cells (WBC) per high power field (HPF)] and the least sensitive was the nitrite test (21.0%). The leukocyte esterase test showed the highest accuracy of 91.1%. CONCLUSION: The study supports the recommendation of the use of oral ciprofloxacin as the first line treatment of uncomplicated UTI by the Ghana Standard Treatment Guidelines (2017). FUNDING: No funding was provided for this study.

Refined PBPK model of aggregate exposure to methyl tertiary-butyl ether.

Aggregate (multiple pathway) exposures to methyl tertiary-butyl ether (MTBE) in air and water occur via dermal, inhalation, and oral routes. Previously, physiologically based pharmacokinetic (PBPK) models have been used to quantify the kinetic behavior of MTBE and its primary metabolite, tertiary-butyl alcohol (TBA), from inhalation exposures. However, the contribution of dermal and oral exposures to the internal dose of MTBE and TBA were not characterized well. The objective of this study was to develop a multi-route PBPK model of MTBE and TBA in humans. The model was based entirely on blood MTBE and TBA measurements from controlled human exposures. The PBPK model consists of nine primary compartments representing the lungs, skin, fat, kidney, stomach, intestine, liver, rapidly perfused tissue, and slowly perfused tissue. The MTBE and TBA models are linked by a single metabolic pathway. Although the general structure of the model is similar to previously published models of volatile organic compounds, we have now developed a detailed mathematical description of the lung, skin, and gastrointestinal tract. This PBPK model represents the most comprehensive and accurate description of MTBE and TBA pharmacokinetics in humans to date. The aggregate exposure model application for MTBE can be generalized to other environmental chemicals under this framework given appropriate empirical measurement data.

Antibiotic prescription pattern in a Ghanaian primary health care facility.

INTRODUCTION: A major challenge to the provision of health care worldwide is the irrational use of antibiotics. To help promote rational use of drugs, standard treatment guidelines (STG) and essential medicine lists and facility-specific formularies have been developed to be used by clinicians. This study assessed the prescription pattern of antibiotics and explored the use of STG by clinicians. METHODS: A prospective cross sectional study that made use of seven core drug use indicators was conducted from February, 2017 to July, 2017. Prescribing indicators were assessed using 388 prescriptions that were submitted for filling and dispensing at the pharmacy unit of the hospital. Clinicians were interviewed to assess their use of STG. Data were analyzed using SPSS version 20.0 with a p-value of < 0.05 considered as statistically significant. RESULTS: A total of 1351 drugs were prescribed for 388 patients. The average number of medicines per prescription was 3.5. Of the 388 prescriptions, 55.2% bore antibiotics, with amoxicillin (22.5%) and ciprofloxacin (18.4%) being the most prescribed antibiotics. Patients' knowledge about their medications was found to be significantly associated with the number of drugs per prescription (p = 0.001), age (p = 0.015) and educational level (p = 0.001). Only 41.7% of prescribers had copies of STG and used them. CONCLUSION: The prescribing and dispensing practices in the hospital were generally not satisfactory with a low patronage of STG among prescribers. In order to improve the situation, clinicians should practice evidence based medicine rather than empirical treatment of conditions as well as use the STG in practice.

Caesarean section in a primary health facility in Ghana: Clinical indications and feto-maternal outcomes.

There is great concern about the increasing rise in the rate of caesarean section in both developed and developing countries. This study was to ascertain the prevalence and compare outcomes of elective and emergency caesarean sections among women who deliver at the University of Cape Coast Hospital, Ghana. This retrospective study reviewed records of 645 women who delivered through caesarean sections during the period of January 2014 and December 2015. The prevalence of caesarean section was 26.9%. There was a significantly higher rate of adverse fetal outcomes (P=0.016) among babies born through emergency caesarean section. There were 12 (1.9%) women who had caesarean section done based on maternal request. The caesarean section rate found in this study was high. The lack of availability of technology for diagnosing fetal distress found in this study could possibly lead to over diagnosis of fetal distress. Thus availability of such diagnostic technology could reduce the high caesarean section rate. The high numbers of women requesting caesarean section without medical indication should be investigated and the motivation factors identified so as to curb the practice.

Relative Susceptibilities of ABO Blood Groups to Plasmodium falciparum Malaria in Ghana.

The clinical outcome of falciparum malaria in endemic areas is influenced by erythrocyte polymorphisms including the ABO blood groups. Studies have reported association of ABO blood group to resistance, susceptibility, and severity of P. falciparum malaria infection. Individuals with blood group "A" have been found to be highly susceptible to falciparum malaria whereas blood group "O" is said to confer protection against complicated cases. We analyzed samples from 293 young children less than six years old with malaria in the Korle-Bu Teaching Hospital in Accra, Ghana. It was observed that group O was present in about 16.1% of complicated cases weighed against 40.9% of uncomplicated controls. Individuals with complicated malaria were about twice likely to be of blood groups A and B compared to group O (A versus O, OR = 1.90, 95% CI = 1.59-2.26, P < 0.0001; B versus O, OR = 1.82. 95% CI = 1.57-2.23, P < 0.0001). Blood group O participants with complicated diseases had low parasitaemia compared to the other blood groups (P < 0.0001). This may give blood group O individuals a survival advantage over the other groups in complicated malaria as suggested. Participants with complicated falciparum malaria were generally anaemic and younger than those with uncomplicated disease.

Quality Assessment of Artemether-Lumefantrine Samples and Artemether Injections Sold in the Cape Coast Metropolis.

Most prescribers and patients in Ghana now opt for the relatively expensive artemether/lumefantrine rather than artesunate-amodiaquine due to undesirable side effects in the treatment of uncomplicated malaria. The study sought to determine the existence of substandard and/or counterfeit artemether-lumefantrine tablets and suspension as well as artemether injection on the market in Cape Coast. Six brands of artemether-lumefantrine tablets, two brands of artemether-lumefantrine suspensions, and two brands of artemether injections were purchased from pharmacies in Cape Coast for the study. The mechanical properties of the tablets were evaluated. The samples were then analyzed for the content of active ingredients using High Performance Liquid Chromatography with a variable wavelength detector. None of the samples was found to be counterfeit. However, the artemether content of the samples was variable (93.22%-104.70% of stated content by manufacturer). The lumefantrine content of the artemether/lumefantrine samples was also variable (98.70%-111.87%). Seven of the artemether-lumefantrine brands passed whilst one failed the International Pharmacopoeia content requirements. All brands of artemether injections sampled met the International Pharmacopoeia content requirement. The presence of a substandard artemether-lumefantrine suspension in the market should alert regulatory bodies to be more vigilant and totally flush out counterfeit and substandard drugs from the Ghanaian market.

Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers.

Methyl tertiary butyl ether (MTBE), a gasoline additive used to increase octane and reduce carbon monoxide emissions and ozone precursors, has contaminated drinking water and can lead to exposure by oral, inhalation, and dermal routes. To determine its dermal, oral, and inhalation kinetics, 14 volunteers were exposed to 51.3 microg/ml MTBE dermally in tap water for 1 h, drank 2.8 mg MTBE in 250 ml Gatorade(R), and inhaled 3.1 ppm. MTBE for 1 h. Blood and exhaled breath samples were then obtained. Blood MTBE peaked between 15 and 30 min following oral exposure, at the end of inhalation exposure, and ~5 min after dermal exposure. Elimination by each route was described well by a three-compartment model (Rsq >0.9). The Akaike Information Criterion for the three-compartment model was smaller than the two-compartment model, supporting it over the two-compartment model. One metabolite, tertiary butyl alcohol (TBA), measured in blood slowly increased and plateaued, but it did not return to the pre-exposure baseline at the 24-h follow-up. TBA is very water-soluble and has a blood:air partition ratio of 462, reducing elimination by exhalation. Oral exposure resulted in a significantly greater MTBE metabolism into TBA than by other routes based on a greater blood TBA:MTBE AUC ratio, implying significant first-pass metabolism. The slower TBA elimination may make it a better biomarker of MTBE exposure, though one must consider the exposure route when estimating MTBE exposure from TBA because of first-pass metabolism. Most subjects had a baseline blood TBA of 1-3 ppb. Because TBA is found in consumer products and can be used as a fuel additive, it is not a definitive marker of MTBE exposure. These data provide the risk assessment process of pharmacokinetic information relevant to the media through which most exposures occur-air and drinking water.

The development and testing of a dermal exposure system for pharmacokinetic studies of administered and ambient water contaminants.

INTRODUCTION: In order to investigate the pharmacokinetics of water-borne chemicals while eliminating exposures by other routes, a dermal exposure system was developed to expose the hand and forearm of human subjects. METHODS: The goal was, primarily, to study the dermal pharmacokinetics of methyl tertiary butyl ether (MTBE), a water contaminant, and, secondarily, the ambient disinfection byproducts (DBPs). MTBE is used as a fuel oxygenate and DBPs result from chlorination of drinking water. The DBPs measured in the water and blood of the subjects were chloroform, bromodichloromethane, and dibromochloromethane. The dermal exposure system was constructed of inert and impervious materials. The interface between the glass and Teflon exposure tank and the subject was custom-made of clear Tedlar (polyvinylfluoride) so that the depth of the arm in the media could be monitored. RESULTS: Sampling of the water concentration of the test chemical, MTBE, demonstrated stability over the duration of the exposure. A temperature loss of about 1.5 degrees C occurred over the course of the 1-h exposure. Blood concentrations taken from 14 human subjects before, during, and after the 1-h exposure demonstrated that measurable MTBE and DBPs were absorbed. DISCUSSION: This system has the advantages of maintaining contaminant concentration and exposing an anatomically distinct body region, and the convenience of blood sampling.

A real-time method to evaluate the nasal deposition and clearance of acetone in the human volunteer.

Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled [(13)C]acetone at approximately 1 ppm concentration for 30 min under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhale mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 s. A second ion-trap mass spectrometer simultaneously sampled from the volunteer's exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the [(13)C]acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart-rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in [(13)C]acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analyses of [(13)C]acetone concentrations indicate that between 40 and 75% of the compound is absorbed upon inhalation and nearly all of that absorbed is released back into the breath stream during exhalation.