Population Pharmacokinetic Modelling of Morphine,Gabapentin and their Combination in the Rat

Purpose

The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles.

Methods

The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied to describe the pharmacokinetics of the compounds and possible interactions.

Results

The plasma-concentration-time profiles of morphine and gabapentin were best described using a three- and a one-compartment disposition model respectively. Dose dependencies were found for morphine absorption rate and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation.

Conclusions

The finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might not have any clinical relevance.

     

Population-based study of acute respiratory infections in children,Greenland

Acute respiratory infections (ARI) are frequent in Inuit children, in terms of incidence and severity. A cohort of 294 children <2 years of age was formed in Sisimiut, a community on the west coast of Greenland, and followed from 1996 to 1998. Data on ARI were collected during weekly visits at home and child-care centers; visits to the community health center were also recorded. The cohort had respiratory symptoms on 41.6% and fever on 4.9% of surveyed days. The incidence of upper and lower respiratory tract infections was 1.6 episodes and 0.9 episodes per 100 days at risk, respectively. Up to 65% of the episodes of ARI caused activity restriction; 40% led to contact with the health center. Compared with studies from other parts of the world, the incidence of ARI appears to be high in Inuit children.     

Renin secretion and total body sodium: Pathways of integrative control

1. Herein, we review mechanisms of sodium balance operating at constant mean arterial blood pressure (MABP); that is, under conditions where MABP does not provide the primary signal to the kidney. 2. Relative constancy of body fluids requires accurate regulation of total body sodium (TBS). Normally, plenty of sodium is ingested and balance is achieved by control of renal excretion driven by multiple central nervous, cardiovascular, endocrine and renal tubular mechanisms. Subtle changes in sodium balance are associated with parallel changes in extracellular volume (due to fast and precise osmoregulation), but not necessarily in MABP. Therefore, signals other than MABP seem to be the primary link between TBS and kidney function. 3. Renal functions involved in sodium homeostasis include: (i) the rate of glomerular filtration (GFR) determined by renal haemodynamics, including tubuloglomerular feedback (TGF); (ii) proximal tubular reabsorption involving glomerulotubular balance (GTB) and neurohumoral control; (iii) macula densa mechanisms influencing TGF and renin secretion; and (iv) distal tubular reabsorption dominated by the renin–angiotensin–aldosterone system (RAAS). 4. The present review focuses on the interactive, homeostatic operation of TBS, MABP, GTB, TGF and the RAAS. Regulation of sodium balance involves neurohumoral control of tubular sodium reabsorption, including proximal reabsorption. Central nervous system‐mediated regulation of the latter modulates renin secretion. Homeostatically, the RAAS–TGF interaction seems analogous to a spring–shock absorber set‐up: non‐adaptive RAAS functions determine the new steady state position, whereas TGF controls the rate of change. Recruitment of renin‐secreting cells during sustained stimulation may be essential for chronic adaptation, although details of this afferent arteriolar cell plasticity are unclear at present.     

What is the association between MRI and conventional radiography in measuring femoral head migration?

Background and purpose — Pelvic radiographs are traditionally used for assessing femoral head migration in residual acetabular dysplasia (RAD). Knowledge of the heightened importance of cartilaginous structures in this condition has led to increased use of MRI in assessing both osseous and cartilaginous structures of the pediatric hip. Therefore, we assessed the relationship between migration percentages (MP) found on MRI and conventional radiographs. Second, we analyzed the reliability of MP in MRI and radiographs.Patients and methods — We retrospectively identified 16 patients (mean age 5 years [2–8], 14 girls), examined for RAD during a period of 2½ years. 4 raters performed blinded repeated measurements of osseous migration percentage (MP) and cartilaginous migration percentage (CMP) in MRI and radiographs. Pelvic rotation and tilt indices were measured in radiographs. Bland–Altman (B–A) plots and intraclass correlation coefficients (ICC) were calculated for agreement and reliability.Results — B–A plots for MP_R and MP_MRI produced a mean difference of 6.4 with limits of agreement –11 to 24, with higher disagreements at low average MP values. Mean MP_R differed from mean MP_MRI (17% versus 23%, p < 0.001). MP_R had the best interrater reliability with an ICC of 0.92 (0.86–0.96), compared with MP_MRI and CMP with ICC values of 0.61 (0.45–0.70) and 0.52 (0.26–0.69), respectively. Intrarater reliability for MP_R, MP_MRI and CMP all had ICC values above 0.75 and did not differ statistically significantly. Differences inMP_MRI and MP_R showed no correlation to pelvic rotation index, pelvic tilt index, or interval between radiograph and MRI exams.Interpretation — Pelvic radiographs underestimated MP when compared with pelvic MRI. We propose CMP as a new imaging measurement, and conclude that it has good intrarater reliability but moderate interrater reliability. Measurement of MP in radiographs and MRI had mediocre to excellent reliability.

MRI scans have been used in the diagnosis and prognostication of developmental dysplasia of the hip (DDH) for the last 30 years (Bos et al. 1988). MRI scans permit the examiner complete control over orientation of the examined pelvis, allowing for more accurate measurements and visualization of non-bony structures. However, conventional pelvic radiographs are still the preferred method of examination for children over the age of 6 months due to financial considerations and challenges in scanning children, such as anxiety of the child and the need for sedation.Residual acetabular dysplasia (RAD) occurs in 3.5–17% of treated cases of DDH (Tucci et al. 1991, Alexiev et al. 2006) and is a known risk factor for secondary osteoarthritis (Malvitz and Weinstein 1994). Indications for corrective surgery for this condition remain controversial, as seen in the tendency of surgeons to undertreat RAD patients who need surgery, rather than overtreat those who do not (Ömeroǧlu et al. 2012).Many radiographic measurements have been proposed to indicate the severity and prognosis of DDH and many are used when deciding which patients should receive corrective surgery. The most commonly used are the osseous acetabular index (OAI) and acetabular head coverage (Ömeroǧlu et al. 2012). None of these measurements, on their own or in combination, have been shown to predict DDH prognosis accurately in all cases, and are therefore most commonly used in various combinations at the discretion of the surgeon. Acetabular head coverage, both cartilaginous and osseous, is of importance for the stability of the hip joint (Bos et al. 1991, Domenech et al. 2001) and is commonly estimated by the osseous migration percentage (MP), first proposed by Reimers (Reimers 1980), and has been shown to be predictive of later osteoarthritis (Terjesen 2011). MP estimates the percentage of the osseous femoral head that is covered by the osseous acetabulum. In this study we emulated the method developed by Reimers, in measuring the percentage of the cartilaginous femoral head covered by the cartilaginous acetabulum, and propose the name: cartilaginous migration percentage (CMP).Currently, there are no studies comparing reliability, agreement, and correlation of MP in radiographs and MRI or between MP and CMP.We compared agreement and correlation of MP measurements in pelvic radiographs and coronal MRI sequences. We assessed values and inter- and intrarater reliability when measuring CMP on pelvic MRI, and evaluated inter- and intrarater reliability when measuring MP on pelvic radiographs and MRI in hips evaluated for RAD corrective surgery.     

Nuclear organization of orexinergic neurons in the hypothalamus of a lar gibbon and a chimpanzee

Employing orexin-A immunohistochemical staining we describe the nuclear parcellation of orexinergic neurons in the hypothalami of a lar gibbon and a chimpanzee. The clustering of orexinergic neurons within the hypothalamus and the terminal networks follow the patterns generally observed in other mammals, including laboratory rodents, strepsirrhine primates and humans. The orexinergic neurons were found within three distinct clusters in the ape hypothalamus, which include the main cluster, zona incerta cluster and optic tract cluster. In addition, the orexinergic neurons of the optic tract cluster appear to extend to a more rostral and medial location than observed in other species, being observed in the tuberal region in the anterior ventromedial aspect of the hypothalamus. While orexinergic terminal networks were observed throughout the brain, high density terminal networks were observed within the hypothalamus, medial and intralaminar nuclei of the dorsal thalamus, and within the serotonergic and noradrenergic regions of the midbrain and pons, which is typical for mammals. The expanded distribution of orexinergic neurons into the tuberal region of the ape hypothalamus, is a feature that needs to be investigated in other primate species, but appears to correlate with orexin gene expression in the same region of the human hypothalamus, but these neurons are not revealed with immunohistochemical staining in humans. Thus, it appears that apes have a broader distribution of orexinergic neurons compared to other primate species, but that the neurons within this extension of the optic tract cluster in humans, while expressing the orexin gene, do not produce the neuropeptide.