Limited sampling strategies for estimation of tacrolimus exposure in kidney transplant recipients receiving extended‐release tacrolimus preparation

Tacrolimus is the key component of most contemporary immunosuppressive drug regimens for the prevention of transplant rejection. Area under the concentration time curve over 24 h (AUC_0–24) predicts efficacy, but predose (trough) tacrolimus blood concentration (C₀) is currently used to guide dosing. In clinical or research situations where an estimate of AUC is required, collection of a full 24 h pharmacokinetic (PK) profile is cumbersome. Limited sampling strategies (LSSs) have been developed for some tacrolimus preparations but not for the new, extended‐release, once‐daily formulation of tacrolimus, ENVARSUS XR. Twenty‐four kidney transplant recipients were enrolled in this study. Twenty‐four tacrolimus PK profiles were obtained over 24 h. Multiple linear regression was used to generate LSSs with the best subset selection for accurate estimation of tacrolimus AUC_0–24. The predictive performance of each model was assessed in the evaluation group. The correlation between actual and predicted AUC_0–24 was evaluated and mean percentage prediction error (MPE%), mean absolute percentage prediction error (MAE%), and root mean squared error (RMSE) were calculated for each prediction model to assess bias and precision. The selected LSSs were highly correlated to AUC_0–24 compared with the correlation between C₀ and AUC_0‐24. Two and three sampling points limited sampling strategies: C₀, C₂, and C₁₀ provide the most reliable and effective LSS for estimation of tacrolimus AUC_0–24 in routine clinic use. These limited sampling models can be applied in therapeutic drug monitoring schemes to personalize tacrolimus dosing for kidney transplant recipients on treatment with extended‐release tacrolimus.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Tacrolimus is a narrow therapeutic index drug with wide pharmacokinetic (PK) variability between individuals. There is evidence that tacrolimus exposure based on blood concentration (C₀) monitoring can vary extensively. Although AUC is considered the best exposure indicator related to tacrolimus clinical effects, tacrolimus C₀ monitoring is the most commonly used method in routine clinical practice. There is no limited sampling strategy (LSS) available for kidney transplant recipients using extended‐released tacrolimus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study assessed different LSSs for an accurate estimation of area under the concentration time curve over 24 h (AUC_0–24) for extended‐released tacrolimus.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Tacrolimus exposure can be accurately measured using two and three sampling points of LSS in kidney transplant recipients using extended‐released tacrolimus.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These LSSs can be applied in therapeutic drug monitoring (TDM) schemes to personalize tacrolimus dosing in routine clinical practice for kidney transplant recipients receiving extended‐released tacrolimus. Moreover, it can be used in PK clinical trials providing an accurate AUC_0–24 estimation. It also can have useful implementation in the new micro‐sampling techniques.     

Synthesis and Characterization of Biopolymeric Chitosan Derived from Land Snail Shells and Its Potential for Pb2+ Removal from Aqueous Solution

Pb²⁺ is considered to be a very toxic pollutant in the aquatic environmental media. Biopolymeric chitosan synthesized from snail shell has been studied for its potential to remove heavy metals from aqueous solution. The experiments were conducted in the range of 1–50 mg/L initial Pb²⁺ concentration at 298 K. The effects of pH, adsorbent dosage and contact time on the adsorptive property of the adsorbent were investigated and optimized. The derived chitosan was characterized using Fourier transform infrared spectrometer (FT-IR) and X-ray florescence (XRF). The experimental data obtained were analysed using the Langmuir and Freundlich adsorption isotherm models. The Langmuir model and pseudo second order kinetic model suitably described the adsorption and kinetics of the process with regression coefficients of 0.99 and 1.00, respectively. Sodium hydroxide was a better desorbing agent than hydrochloric acid and de-ionized water. From the results obtained, it is concluded that synthesized biopolymers from land snail shells has the potential for the removal of Pb²⁺ from aqueous solutions.     

Toxic catheters and urethral strictures: A concern about types of catheters used in resource-poor countries

Various reports in the literature have confirmed urethral toxicity caused by the use of catheters, mostly latex catheters and their coated versions, resulting in long-segment urethral strictures or strictures located in multiple areas of the urethra. Most catheters used in resource-poor countries, such as Nigeria, are latex catheters with various coatings, such as silicone. The reasons for the widespread use of these potentially toxic catheters are mainly non-availability and/or the high cost of less toxic catheters. We report three cases of urethral strictures following the use of siliconized latex catheters in order to highlight the potential urethral toxicity associated with the use of latex catheters and to draw the authorities’ attention to the need to regulate the types of catheters used in the country.     

Alcohol,cognitive impairment and the hard to discharge acute hospital inpatients

Aim  To examine the role of alcohol and alcohol-related cognitive impairment in the clinical presentation of adults in-patients less than 65 years who are ‘hard to discharge’ in a general hospital. Method  Retrospective medical file review of inpatients in CUH referred to the discharge coordinator between March and September 2006. Results  Of 46 patients identified, the case notes of 44 (25 male; age was 52.2 ± 7.7 years) were reviewed. The average length of stay in the hospital was 84.0 ± 72.3 days and mean lost bed days was 15.9 ± 36.6 days. The number of patients documented to have an overt alcohol problem was 15 (34.1%). Patients with alcohol problems were more likely to have cognitive impairment than those without an alcohol problem [12 (80%) and 9 (31%) P = 0.004]. Patients with alcohol problems had a shorter length of stay (81.5 vs. 85.3 days; t = 0.161, df = 42, P = 0.87), fewer lost bed days (8.2 vs. 19.2 days; Mann–Whitney U = 179, P = 0.34) and no mortality (0 vs. 6) compared with hard to discharge patients without alcohol problem. Conclusion  Alcohol problems and alcohol-related cognitive impairment are hugely over-represented in acute hospital in-patients who are hard to discharge. Despite these problems, this group appears to have reduced morbidity, less lost bed days and a better outcome than other categories of hard to discharge patients. There is a need to resource acute hospitals to address alcohol-related morbidity in general and Wernicke–Korsakoff Syndrome in particular.     

Teething myths among nursing mothers in a Nigerian community

Background:

Many symptoms had been associated with teething in children with the possibility of overlooking potentially fatal condition. Symptoms that had been associated with teething include diarrhoea, fever, vomiting and cough. The possibility that any of these symptoms could have been due to other causes call for thorough investigation of the child before concluding that it is only “teething”.

Objectives:

The study was carried out to assess the beliefs of nursing mothers concerning symptoms that are associated with teething among children and to identify those that would seek medical treatments in case of their children having such symptoms during teething.

Materials and Methods:

Two hundred and ninety nursing mothers whose children had erupted at least a tooth were interviewed in the immunisation clinics of the University College Hospital and Adeoyo Maternity Teaching Hospital, both in Ibadan, Nigeria, on their beliefs and practice concerning teething in children.

Results:

One hundred and eighty-eight (64.8%) of the mothers associated symptoms such as fever, cough, catarrh and diarrhoea with eruption of teeth in their children. Over half of the women agreed that a child having either fever (51.0%), ear infection (57.6%) or cough (50.3%) should be promptly taken for medical consultation and not be tagged “teething”, while for other symptoms such as gum pain (74.5%), sleepless night (56.6%), vomiting (51.4%) and diarrhoea (51.7%), over half of the mothers believed that the symptoms will resolve following the eruption of the teeth.

Conclusion:

The study demonstrated that mothers in the study attributes several symptoms to teething, which could be detrimental to the survival of their children as the symptom could have been due to other causes. There is, therefore, need for public enlightenment to create awareness on the possible effect of presumptuous belief that childhood diseases are due to teething process.     

Local knowledge,use pattern and geographical distribution of Moringa oleifera Lam. (Moringaceae) in Nigeria

Ethno-pharmacological relevance

All parts of Moringa oleifera are medicinally valuable with overlapping uses in treating myriads of ailments and diseases including body pains and weakness, fever, asthma, cough, blood pressure, arthritis, diabetes, epilepsy, wound, and skin infection. Moringa also has robust ability to challenge terminal diseases such as HIV/AIDs infections, chronic anemia, cancer, malaria and hemorrhage. The present study was to obtain ethnobotanical information on the use and local knowledge variation, geographical distribution, and to collect different landraces of Moringa oleifera from the different agro-ecological regions in Nigeria, for further studies.

Materials and methods

Ethnobotanical data were collected through face to face interviews, semi structured questionnaires and discussions with selected people who had knowledge about the plant. The fidelity level (FL %) and use value for different use categories of Moringa oleifera and its parts were estimated. The variation in ethnobotanical knowledge was evaluated by comparing the mean use value among ethnic, gender and age groups using sample T test. Garmi GPS was used to determine the locations (latitude and longitude) and height in different areas to assess the geographical spread of the species.

Results

Seven (7) categories of use (Food, medicine, fodder, fencing, firewood, gum and coagulant) were recorded for Moringa oleifera. Food and medicinal uses showed highest fidelity level while the leaves and the seeds were the plant parts most utilized for the same purposes. There were significant differences among the ethnic, gender and age groups regarding the ethno-botanical use value. The geographical distribution pattern shows that the Moringa oleifera is well distributed in all ecological zones of Nigeria, well adapted to the varied climatic conditions and gaining unprecedented awareness among the people.

Conclusion

Though considered an introduced species, Moringa oleifera has found wide acceptance, recognition and usefulness among the various ethnicities in the studied areas. The sources of introduction, domestication and ethnic differentiation influenced the distribution pattern across the geographical areas.     

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole-genome or whole-exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60–85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h² = 0.575, p = 0.010) and the combined APOBEC signatures (h² = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21–0.45) of APOBEC signature contribution at genome-wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10⁻⁶). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.