The method of averaging applied to pharmacokinetic/pharmacodynamic indirect response models.

The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MAv) in the appropriate circumstances. The MAv gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.e. repeats its values in regular intervals) and the rate of change of the PD response is such that it is approximately constant over a single period of the PK profile. This paper explains the basis of the MAv by means of a simple mathematical derivation. The NONMEM® implementation of the MAv using the abbreviated FORTRAN function FUNCA is described and explained. The application of the MAv is illustrated by means of an example involving changes in glycated hemoglobin (HbA1c%) following administration of canagliflozin, a selective sodium glucose co-transporter 2 inhibitor. The PK/PD model applied to these data is fitted with NONMEM® using both the MAv and the standard method using a numerical differential equation solver (NDES). Both methods give virtually identical results but the NDES method takes almost 8 h to run both the estimation and covariance steps, whilst the MAv produces the same results in less than 30 s. An outline of the NONMEM® control stream and the FORTRAN code for the FUNCA function is provided in the appendices.

Outbreak of epidemic dropsy in Ethiopia: the clinical and therapeutic observation.

INTRODUCTION: Epidemic dropsy results from ingestion of argemone oil contaminated food staffs. The oil from Argemone Mexican seeds contains toxic alkaloids called sanguinarine and dehydrosangunarine. These cause wide spread capillary dilatation, proliferation and leakages. This leads to oedema, hypovolemia and hypotension. OBJECTIVE: To describe the socio-demographic and clinical manifestations of the patients affected with epidemic dropsy in Tikur Anbessa specialized Hospital (TASH). METHODS: A case series study was conducted in an outbreak with unusual cases which was later diagnosed to be epidemic dropsy. Clinical evaluation of suspects was done and optimal therapy given for the complications detected and information was filled in structured format by medical residents and medial chart records review was made for occurrence of new complications in the end of 9 months. RESULTS: A total of 164 patients were seen at TASH from 26 households, in 8 sub-cities of Addis Ababa. A wide range of age group was affected with 70% from 16 to 40 years of age. There was no case among less than 5 years of age. Females were affected more than threefold as compared to males. All the patients manifested with bilateral leg swelling and pitting oedema. It was tender in 50 (30.4%) of them while 43 (26.2%) had erythema. Tachycardia was the next common manifestation occurring in 135 (82.3%), followed by cough in 123 (75%), anaemia in 59 (36%), headache in 58 (35.4%), shortness of breathing in 52 (31.2%), hair loss in 44 (26.8%) and respiratory distress in 35 (21.3%). Abdominal pain, hepatomegally, nausea and vomiting were also seen. There was abnormality in the chest X-ray of 31 (27.2%). Hair loss, tingling and burning extremities, difficulty of standing, hyperpigmentation, pruritic rash and eye symptoms were observed lately during follow up. Five of the patients died while in hospital care due to acute respiratory distress syndrome (ARDS). CONCLUSIONS: The commonest clinical manifestation in our patients is bilateral leg swelling which is similar to other outbreaks of epidemic dropsy elsewhere. The mortality rate is also comparable with other series but all cases died by ARDS in our series which is unusual in other reports. As this is the first reported epidemics in Ethiopia the findings will create awareness of clinical features of epidemic dropsy among clinicians, and therefore, helps for diagnoses of similar problems in the future.