Hybrid Pharmacokinetic Models to Describe Anti-HIV Nucleoside Brain Disposition Following Parent and Prodrug Administration in Mice

Brain delivery of active anti-HIV compounds is important for successful treatment of the AIDS patient. As an initial step in predicting human brain drug concentrations, hybrid pharmacokinetic models were developed to characterize the disposition of anti-HIV nucleosides following parent and prodrug administrations in mice. Mouse data were obtained following intravenous administration of 3-azido-2,3-dideoxyuridine (AZddU or AZDU), 3-azido-3-deoxythymidine (AZT), and their dihydropyridine prodrugs (AZddU-DHP and AZT-DHP). Exponential equations were fitted to the serum concentration–time data for each species, including the pyridinium ion moieties, and subsequently used in differential mass balance equations describing the brain dynamics of each compound. Model parameters for the mass balance equations were estimated by various techniques, including the utilization of in vitro data. In general, model-predicted brain concentrations agreed with the observed data. Similar data in larger animals will permit scale-up of the current model to predict human brain drug concentrations.     

Global health: A lasting partnership in paediatric surgery

Background:

To emphasise the value of on-going commitment in Global Health Partnerships.

Materials and Methods:

A hospital link, by invitation, was set up between United Kingdom and Tanzania since 2002. The project involved annual visits with activities ranging from exchange of skill to training health professionals. Furthermore, the programme attracted teaching and research activities. For continuity, there was electronic communication between visits.

Results:

Six paediatric surgeons are now fully trained with three further in training in Africa. Paediatric surgery services are now separate from adult services. Seven trainee exchanges have taken place with four awarded fellowships/scholarships. Twenty-three clinical projects have been presented internationally resulting in eight international publications. The programme has attracted other health professionals, especially nursing and engineering. The Tropical Health and Education Trust prize was recently achieved for nursing and radiography. National Health Service has benefited from volunteering staff bringing new cost-effective ideas. A fully funded medical student elective programme has been achieved since 2008.

Conclusion:

Global Health Partnerships are an excellent initiative in establishing specialist services in countries with limited resources. In the future, this will translate into improved patient care as long as it is sustained and valued by long term commitment.Key words: Global health, global paediatric surgery, paediatric surgery     

An OxPLORE Initiative Evaluating Children’s Surgery Resources Worldwide: A Cross-sectional Implementation of the OReCS Document

World Journal of Surgery - The Global Initiative for Children's Surgery (GICS) group produced the Optimal Resources for Children’s Surgery (OReCS) document in 2019, listing standards of...     

An Observational Study of Paediatric Preoperative Transfusion Practice in a Resource-Limited Setting

World Journal of Surgery - Paediatric anaemia is highly prevalent in low–middle-income countries and can negatively impact postoperative outcomes. Currently, there are no guidelines for the...     

Effect of mannitol and furosemide on plasma osmolality and brain water

BACKGROUND: Mannitol and furosemide are used to reduce increased intracranial pressure (ICP) and to reduce brain bulk during neurosurgery. One mechanism by which these changes might occur is via a reduction in brain water content. Although mannitol and furosemide are commonly used in combination, there has been no formal evaluation of the interactive effects of these two drugs on brain water. The effect of mannitol and furosemide alone and in combination on water content of normal rat brain was examined. METHODS: The lungs of rats anesthetized with halothane were mechanically ventilated to maintain normal physiologic parameters. After baseline measurement of plasma osmolality, mannitol (1, 4, or 8 g/kg), furosemide (2, 4, or 8 mg/kg), or a combination of furosemide (8 mg/kg) and mannitol (1, 4, or 8 g/kg) was administered intravenously over approximately 15 min. One hour later, plasma osmolality was measured, the animals were killed, and brain water content was determined by wet and dry weight measurements. RESULTS: Mannitol produced a dose-dependent increase in plasma osmolality and reduction of brain water content. There was a linear relation between plasma osmolality and brain water content. Furosemide alone did not affect plasma osmolality or brain water at any dose. The combination of furosemide with mannitol resulted in a greater increase in plasma osmolality than seen with mannitol alone and a greater decrease in brain water at 4 and 8 g/kg of mannitol. CONCLUSIONS: The doses of mannitol and furosemide utilized were much larger than clinically applicable doses and were selected to maximize the ability to detect effect on brain water. The combination of mannitol and furosemide resulted in greater reduction of brain water content than did mannitol alone. Furosemide enhanced the effect of mannitol on plasma osmolality, resulting in a greater reduction of brain water content. Potential interaction (if any) of smaller, clinically used doses of mannitol and furosemide cannot be surmised from the current study.     

Prenatally diagnosed portocaval shunt and postnatal outcome: a case report

Congenital absence of the portal vein (CAPV) is a rare anomaly in the form of a portocaval shunt, whereby the intestinal and splenic venous drainage bypasses the liver and drains directly into the systemic circulation. We report a case of CAPV diagnosed prenatally after the recognition of a dilated umbilical vein draining directly into a large inferior vena cava (IVC). The IVC then drained into the right atrium of a dilated, hyperdynamic heart. The ductus venosus could not be identified. Repeated postnatal scans showed a gradual disappearance of venous lakes in the region of the porta hepatis and a clear drainage of the splenic vein to the left renal vein and the superior mesenteric vein to the IVC. From birth up to twelve months follow-up there was no evidence of liver dysfunction, encephalopathy or liver lesions.     

Diagnosis at dusk: Malignant hypertension and phaeochromocytoma in a 6‐year‐old girl

Phaeochromocytoma is a rare catecholamine‐secreting tumour that may arise at any age, but is particularly unusual in childhood. The case of a 6‐year‐old girl who presented with a prolonged history of general malaise, headaches and abdominal pain is reported. On examination, she was noted to have malignant hypertension. Subsequent imaging of the abdomen demonstrated a left adrenal mass, with the diagnosis of phaeochromocytoma being confirmed by serial raised urinary metanephrines. Sympathetic blockade was established prior to definitive surgical treatment, resulting in complete resolution of the patient's symptoms and hypertension. Genetic screening of the family has since identified a previously undocumented missense mutation in the patient's VHL gene. The case raises the importance of routine measurement of blood pressure in all paediatric patients regardless of age, presentation or other factors.     

Antenatally suspected congenital cystic adenomatoid malformation of the lung: postnatal investigation and timing of surgery

Background

We have previously reported the outcome of a cohort of cases over a 10-year period with antenatally suspected congenital cystic adenomatoid malformation (CCAM) and have recommended elective surgery within the first year of life for persistent, asymptomatic cases because of the risk of long-term complications. The aims of this study were to document optimal postnatal investigation and timing of surgery.

Methods

Cases were identified using the Oxford Congenital Anomaly Register, theatre records, and histopathology reports. Nineteen cases from 2003 onwards were reviewed with respect to postnatal imaging with chest x-ray and computed tomography scan and timing of surgery.

Results

Chest x-ray was poor at detecting CCAM with only 61% sensitivity. Computed tomography scan was 100% sensitive with no false-positive diagnoses.Of the 19 cases since 2003, 13 cases were asymptomatic and had elective surgery. Eight had surgery at 6 months of age or older, and of these, 4 (50%) had evidence of chronic inflammation/infection on histology including 1 case with multiple abscesses found at surgery and 1 case with multiple adhesions. Five cases had surgery at less than 6 months of age and only 1 of these, aged 5.5 months, had evidence of infection present at histology.

Conclusions

All cases of antenatally suspected CCAM should be followed up postnatally and investigated with computed tomography scan. Elective surgery in asymptomatic cases, at around 3 to 6 months of age, is recommended for persistent lesions because of the risk of long-term complications.