Therapeutic drug monitoring of vancomycin in surgical patients using a validated HPLC method.

BACKGROUND: Vancomycin is being used for the treatment of a variety of infections caused by methicillin resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus. Therapeutic drug monitoring (TDM) is highly recommended for ensuring the safe and effective therapy with vancomycin. A reliable and cost-effective bioanalytical method is required for TDM as well as pharmacokinetic studies of vancomycin. MATERIALS AND METHODS: A selective, sensitive, and cost effective HPLC method was developed and validated for quantification of vancomycin concentrations in human plasma. The mobile phase was a mixture of buffer (50 mM ammonium dihydrogen phosphate, pH 2.4) and acetonitrile 88 : 12 v/v. The separation was carried on C18 column (125 × 4.6 mm, particle size 5 µm) with isocratic flow rate of 0.370 mL/min at room temperature with UV detection at 215 nm. The method was validated for sensitivity, accuracy, and precision as well as stability of vancomycin in human plasma by following European Medicine Agency (EMA) guideline. Therapeutic drug monitoring of vancomycin was performed by quantifying the trough concentrations of vancomycin in 65 human plasma samples after administration of therapeutically relevant dose. RESULTS: The developed method was sensitive enough to quantify vancomycin concentrations as low as 0.25 mg/L in human plasma. Moreover, the method was proved accurate and precise in terms of quantifying the unknown concentration of vancomycin. The evaluation of short-term, long-term, and freeze-thaw stability proved the stability of vancomycin in human plasma. The TDM of vancomycin by using this method showed that 39 (60%) samples were within the target trough concentration range (TTCR), i.e. 10 - 20 mg/L, while 23 samples (35.4%) were below the TTCR, and 3 samples (4.6%) were above this range. CONCLUSION: The developed method is sensitive and cost effective for quantification of vancomycin in human plasma. The results of sample analysis shows that the developed method can be used reliably for TDM of vancomycin.

Population pharmacokinetics of meropenem among post-operative patients in Pakistan.

BACKGROUND: Meropenem, a potent carbapenem is considered the first choice for the empirical treatment of severe infections. Being a hydrophilic drug, more than 83% of the administered dose is eliminated through the renal route, and therefore, the kidney status of the patient may have a significant effect on meropenem clearance (CL). MATERIALS AND METHODS: The data of 205 samples obtained from 59 patients treated with meropenem at the General Hospital Lahore, Pakistan, was used for the development of a population pharmacokinetic (-popPK) model by using nonlinear mixed-effects modeling software. The effect of age, body weight, creatinine clearance (CRCL), and gender was observed on meropenem CL through a stepwise covariate modeling approach. Simulations of 1,000 mg q8h and 1,500 mg q12h over 3-hour infusion were performed based on the renal status of the patients. RESULTS: A two-compartment model was used for popPK analysis, and the values of the pharmacokinetic parameters for CL, V1, V2, and Q were 12.2 L/h, 21.7 L, 7.74 L, and 3.28 L/h, respectively. Meropenem CL was significantly influenced by CRCL, while no significant effect of body weight, age, and sex was observed. Both simulated dosage regimens were equally effective if CRCL of the patient was ≤ 100 mL/min, while 1,000 mg q8h produced better results if CRCL was > 100 mL/min. CONCLUSION: The CL of meropenem depends on the renal status of the patients. The model can be used for dosing simulations based on the CRCL of the patients in order to tailor the dose of meropenem in Pakistani patients.

Population pharmacokinetics of ciprofloxacin in Pakistani patients suffering from enteric fever.

BACKGROUND: Ciprofloxacin, a potent carboxy-fluoroquinolone is proved to be effective against some resistant strains of Gram-negative bacteria. Being a hydrophilic drug, it is primarily excreted through the kidney; almost 66% of the clearance from the body occurs through glomerular filtration. Therefore, renal status of the patient can have a significant effect on ciprofloxacin clearance. MATERIALS AND METHODS: A total of 158 samples were collected from 32 patients treated with ciprofloxacin in the Surgical Unit-I of Lahore General Hospital, Pakistan. The data was used for the development of a population pharmacokinetic model by using non-linear mixed-effect modeling (NONMEM) software. The influence of different covariates (age, sex, body weight, serum creatinine (SeCR), and creatinine clearance (CRCL)) was observed on ciprofloxacin clearance (CL) and volume of distribution (Vd) by stepwise covariate modeling (SCM). RESULTS: A one-compartment model was used for ciprofloxacin population pharma-cokinetik (popPK) analysis, and the values for ciprofloxacin CL and Vd in the final model were estimated at 19.8 L/h and 74.9 L, respectively. Among all the tested covariates, only CRCL was proven to have significant influence on ciprofloxacin CL. CONCLUSION: A strong relationship was found between the ciprofloxacin CL and renal status of the patients. The model can be used for dose tailoring in patients based on their CRCL values before the start of therapy with ciprofloxacin among Pakistani patients.

Giant lipoma of submandibular region; an unusual presentation.

Lipomas in the submandibular region are very uncommon. Large submandibular neck mass (greater than 10 cm) with a rapid growth rate, may raise concern about possible malignancy of salivary glands. Failure to distinguish salivary gland tumour and liposarcoma from a lipoma may represent a medico-legal pitfall. It is very important for the surgeon to rule out liposarcomas when dealing with giant lipomas in such regions. We report a case of a 65-year-old male who presented in the OPD with complains of pain and a 15x12 cm, giant submandibular solitary lipoma of anterior neck which had rapidly increased in size. The diagnosis of lipoma was confirmed on physical examination, radiological investigations and Fine Needle Aspiration Cytology (FNAC). The Patient underwent surgical excision. The surgery produced excellent cosmetic results and no functional impairment. This study illustrates the literature regarding aetiology, epidemiology, followed by diagnostic and treatment modalities of submandibular lipomas.

Fodder cutter (Tokka) injuries: A preventable morbidity.

Pakistan is an agricultural country where fodder cutter (Tokka) is a commonly used machine on the farms. While using it, farmers often meet with accidents causing injuries which are disastrous, and mainly involve the young generation often causing lifelong disability. This is a hospital-based case series, conducted from June 2018 to January 2019 in the Department of Surgery, Lahore General Hospital, Lahore. For this study the patient's demographic data, site of injury, procedure performed and post-operative outcome were recorded. The study includes a total of 30 cases of tokka injury, (23 males and 07 females) with median age of 25 years. Most commonly injured part of the body was the upper limb, in 26 patients, while the lower limb was involved in 2 patients. There were 18 amputations, 8 stumps formation and 4 debridements. Out of the 18, 9 had to be amputated at the wrist, and 9 amputations were performed higher than the wrist. Post-op recovery was uneventful in all cases. Measures such as safer machine design and education of farmers about the safety procedures can significantly avoid these tragedies.

The spectrum of injuries from motorcycle induced road traffic accidents from level one trauma center: A prospective observational study.

OBJECTIVE: To observe the role of motorcycles in causing Road Traffic Accidents and assess the demographics of the drivers, the injury patterns and their outcomes. METHODS: This prospective observational study was conducted at the Surgical Unit 1, Lahore General Hospital, Lahore for a period of 6 months from November 2017 to May 2018. All patients presenting in ER with RTA secondary to motorcycle trauma were included in the study. Data of patients including demographic and medical data, helmet use, spectrum of injuries, specific injury diagnosis, and final disposition of patients was analyzed. The distribution and associations of both victim- and crash-related variables such as crash mechanism, types of involved vehicles, types of injuries, and demographic characteristics were investigated. Data were analyzed by SPSS v23. RESULTS: A total of 835 patients were included in this study with 685 (82%) being male (mean age 28.38 ± 13.89 years) and775 (92.7%) were motorcycle users. The majority of road traffic crashes, traffic accident's mechanism were motorcycle-vehicle accident 579 (69.3%), followed by collision with slow moving carts and bicycles 104 (12.5%). Inner city main roads were the site for 563 (67.4%) accidents. Only 168 (2.2%) patients were wearing helmets at the time of trauma. CONCLUSIONS: Motorcycle traffic morbidities and mortalities remain to be a major public health issue in Lahore as well as all over Pakistan. There is an urgent need for an efficacious interventional programs to decline the burden of motorcycle related morbidity and mortalities.

Formulation of Phaseolus vulgaris L. cream and its characterization.

Red kidney beans have antioxidant effect and thereby can help in skin smoothening, moisturizing, whitening and have anti-wrinkles effect. The study was based on the formulation of a stable w/o emulsion possessing extract of Phaseolus vulgaris L. seeds, using paraffin oil with the aim to investigate its effect on various skin parameters. The extract, achieved by concentrating ethanolic extract of red kidney beans was embedded in the internal aqueous part of w/o emulsion. An active formulation possessing concentrated extract of red kidney beans and a placebo formulation having no active material in the aqueous phase were formulated and placed at various conditions for the duration of 28 days, to observe the stability of cream. The placebo and formulation were stable at different storage conditions in terms of phase separation and colour changes. Minute liquefaction was observed from 21stday up to 28th day in formulations which were kept at 40°C +75% RH (relative humidity). With the passage of time significant changes were observed in formulation pH while insignificant changes were observed at basic pH. Different effects of creams i.e., placebo and formulations were observed on the human skin by applying them on the volunteer's cheeks for about 8 weeks. A stable w/o emulsion can be formulated by using red kidney beans' extract without any phase separation, liquefaction and colour change over 28 days storage.

Comparative pharmacokinetics of valproic acid among Pakistani and South Korean patients: A population pharmacokinetic study.

PURPOSE: The pharmacokinetics of valproic acid have been evaluated in a variety of populations however, the comparison in two different populations was yet to be reported. This study is aimed to compare the pharmacokinetics of valproic acid in Pakistani and South Korean patients. METHOD: The therapeutic drug monitoring (TDM) data of valproic acid from 92 Pakistani patients with 218 samples was combined with the data of 99 South Korean patients with 335 samples in order to form a pooled dataset of 191 patients with 553 samples. Population pharmacokinetic model was developed on NONMEM® software by using first order conditional estimation method for estimation of pharmacokinetic parameters. The influence of different covariates including ethnicity was evaluated the stepwise covariate modelling. The final model was evaluated for predictive performance and robustness by using goodness of fit plots and bootstrap analysis respectively. RESULTS: The data was better described by one compartment model with first order elimination. The value for clearance (CL) of valproic in pooled data was 0.931 L/h with 43.4% interindividual variability (IIV) while volume of distribution (Vd) was 16.6 L with 22.3% IIV. In covariate analysis, ethnicity and body weight were significant covariates for CL while body weight was also significant for Vd. CONCLUSION: A significant difference in CL of valproic acid among Pakistani and South Korean patients was observed. The model can be used for the dose tailoring of valproic acid based on ethnicity and body weight of Pakistani and South Korean patients.

Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan.

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan. Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration-time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks. Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively. Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

Comparative pharmacokinetics of levofloxacin in healthy volunteers and in patients suffering from typhoid Fever.

The aim of this study was to characterize the effect of typhoid fever on pharmacokinetic parameters of levofloxacin (LF) and compare the pharmacokinetic parameters of the said antibiotic in healthy human volunteers and patients with typhoid fever. Total of 12 subjects were divided into two groups "A" (healthy volunteers) and "B" (typhoid patients). Single oral dose of LF 500 mg was given and 5 mL of blood was collected from each subject at 0, 0.25, 0.5, 1, 2, 3, 6, 12, 24, 36 and 72 h. Plasma concentrations of LF were measured by HPLC. Pharmacokinetic parameters were calculated from plasma concentration-time data by using MW/PHARM pharmacological analysis. In healthy volunteers, the average pharmacokinetic parameters were as Cmax (6.79 µg/mL), Tmax (1.84 h), T(½) (10.03 h), Ka (2.23 h(-1)), AUC (110.09 µgh/mL), Vd (85.84 L), Cl (4.57 L/h) and in typhoid patients were Cmax (6.90 µg/mL), Tmax (1.82 h), T(½) (9.42 h), Ka (2.21 h(-1)), AUC (105.55 µgh/mL), Vd (64.31 L), Cl (4.75 L/h). The difference between pharmacokinetic parameters of LF in healthy human volunteers and typhoid patients was calculated by using unpaired t-test. As the p-value in case of all pharmacokinetic parameters was more than 0.05, the difference between pharmacokinetic parameters in both healthy human volunteers and typhoid patients was insignificant. It is concluded that there is no need to adjust the dose of LF in typhoid patients.