Mediators of medication adherence and glycaemic control and their implications for direct outpatient medical costs: a cross-sectional study.

AIMS: To investigate the effects of diabetes-related distress and perception of hyperglycaemia on self-reported medication adherence and glycaemic control, as measured by HbA1c , and to compare the cost outcomes in patients with sub-optimally vs uncontrolled Type 2 diabetes mellitus. METHODS: We conducted a retrospective cross-sectional study that involved the review of a chronic disease database in Singapore. Data on clinical characteristics, diabetes-related distress, perception of hyperglycaemia, self-reported medication adherence and costs were obtained from the database. Mediation analyses were conducted using a linear regression-based approach. A final path model was built to illustrate the sequential mediating effects of diabetes-related distress and perception on the association of medication adherence and HbA1c concentration. RESULTS: Diabetes-related distress and perception of hyperglycaemia were significantly associated with medication adherence and HbA1c concentration. Mediation analyses showed a significant indirect effect of diabetes-related distress and perception of hyperglycaemia on medication adherence and HbA1c concentration. People with uncontrolled diabetes were found to incur significantly higher total direct medical costs than those with sub-optimally controlled diabetes (P = 0.034), with medication cost as the main cost driver (66.6%). CONCLUSIONS: Identifying the influence of the sequential mediating effects of distress and perception was important in understanding the pathway between medication adherence and glycaemic control. This suggests the importance of a team-based approach to address these mediators and thus improve glycaemic control. Poor glycaemic control was also found to be associated with higher direct medical costs.

Impact of pharmacist-involved collaborative care on the clinical, humanistic and cost outcomes of high-risk patients with type 2 diabetes (IMPACT): a randomized controlled trial.

WHAT IS KNOWN AND OBJECTIVE: With the increasing prevalence of diabetes, the physician-centred model is challenged to deliver holistic care in Asia. Diabetes may be managed effectively within a multidisciplinary collaborative care model; however, evidence on its effectiveness in Asian patients is lacking. Therefore, the primary objective was to evaluate the clinical outcomes of multidisciplinary collaborative care vs physician-centred care in diabetes. The secondary objectives were to evaluate humanistic and economic outcomes among the two types of care. METHODS: This 6-month prospective, open-label, parallel-arm, randomized, controlled study was conducted at four outpatient healthcare institutions. High-risk patients aged ≥21 years with uncontrolled type 2 diabetes, polypharmacy and comorbidities were included. Patients with type 1 diabetes or those who were unable to communicate independently were excluded. The control arm received usual care with referrals to nurses and dietitians as needed. The intervention arm (multidisciplinary collaborative care) was followed up with pharmacists regularly, in addition to receiving the usual care. The primary outcomes included HbA1c, systolic blood pressure, low-density lipoprotein and triglycerides. The secondary outcomes included scores from the Problem Areas in Diabetes (PAID) and the Diabetes Treatment Satisfaction Questionnaires (DTSQ), and diabetes-related health service utilization rates and costs. RESULTS AND DISCUSSION: Of 411 eligible patients, 214 and 197 patients were randomized into the intervention and control arms, respectively. At 6 months, 141 patients in the intervention arm (65.9%) and 189 patients in the control arm (95.9%) completed the study. Mean HbA1c reduced from 8.6%±1.5% at baseline to 8.1%±1.3% at 6 months in the intervention arm (P=.04), with up to mean HbA1c improvement of 0.8% in patients with greater levels of uncontrolled glycemia. Whereas the mean HbA1c in the control arm remained unchanged (8.5%±1.4%) throughout the 6-month period. Improvements in PAID and DTSQ scores, reduction in physician workload and an average cost savings of US$91.01 per patient were observed in the intervention arm over 6 months. WHAT IS NEW AND CONCLUSIONS: The positive clinical, humanistic and economic outcomes highlighted the value of multidisciplinary collaborative care for Asian diabetic patients, thereby supporting the effectiveness of this approach in managing chronic diseases.

Gastric rupture after awake fibreoptic intubation in a patient with laryngeal carcinoma.

An 86-yr-old man with recurrent laryngeal carcinoma developed gastric rupture after awake fibreoptic intubation before induction of general anaesthesia. Early clinical signs included a distended, tense and tympanic abdomen with pain and massive pneumoperitoneum (chest radiograph). Laparotomy revealed a 4-cm longitudinal perforation along the lesser curvature of the stomach. This case represents a rare but severe complication that may occur during fibreoptic intubation in the awake patient.

Role of the superior colliculus in the motor effects of cannabinoids and dopamine.

We studied the cellular distribution of CB1 cannabinoid receptors in the superior colliculus of the rat using an antibody raised against the N-terminal of the receptor. The effect of unilateral cannabinoid receptor stimulation in the intermediate layers of the superior colliculus on rotational behavior in rats was also explored. The antibody against CB1 receptors outlined the crossed descending system of the superior colliculus (predorsal bundle output system) as well as the collicular commisure. The potent cannabinoid agonist CP55,940 (5 microgram/0.25 microliter) induced strong contralateral turning when microinjected unilaterally into the lateral intermediate layers of the superior colliculus. The levels of turning obtained with the intracollicular administration of the cannabinoid were comparable to the highest levels obtained with dopamine agonists in the basal ganglia. The D(2) dopamine agonist quinpirole or the D(1) dopamine agonist SKF82958 reversed this contralateral rotation but failed to affect motor behavior on their own. A new motor pathway for cannabinoids is discussed.

Transient periventricular echodensities and developmental outcome in preterm infants.

The outcome of very low-birth-weight infants is reported in relation to neonatal cerebral ultrasound findings. Routine cerebral ultrasound scans were performed in all 147 very low-birth-weight infants admitted to the authors' neonatal intensive care unit from January 1995 to June 1997. Group 1 consisted of 22 infants without ultrasound abnormalities, group 2 consisted of 32 infants with transient periventricular echodensities, and group 3 consisted of 15 infants with intraventricular hemorrhage. Neurologic status was recorded at follow-up visits at the corrected age of 6 and 12 months, and the infants were evaluated further using the Bayley Scales of Infant Development II. More infants in groups 2 and 3 appeared to have significant and mild motor developmental delays than infants in the control group (group 1) at the corrected age of 1 year (P = 0.001). Furthermore, more infants in group 3 appeared to have significant motor developmental delays than did infants in group 2 at the corrected age of 1 year (15% vs 3%). Infants with transient periventricular echodensities and intraventricular hemorrhage have an increased risk of delayed developmental outcome. Infants with transient periventricular echodensities have a more favorable prognosis than do the infants with intraventricular hemorrhage.

Pain modulation by release of the endogenous cannabinoid anandamide.

Synthetic cannabinoids produce behavioral analgesia and suppress pain neurotransmission, raising the possibility that endogenous cannabinoids serve naturally to modulate pain. Here, the development of a sensitive method for measuring cannabinoids by atmospheric pressure-chemical ionization mass spectrometry permitted measurement of the release of the endogenous cannabinoid anandamide in the periaqueductal gray (PAG) by in vivo microdialysis in the rat. Electrical stimulation of the dorsal and lateral PAG produced CB1 cannabinoid receptor-mediated analgesia accompanied by a marked increase in the release of anandamide in the PAG, suggesting that endogenous anandamide mediates the behavioral analgesia. Furthermore, pain triggered by subcutaneous injections of the chemical irritant formalin substantially increased the release of anandamide in the PAG. These findings indicate that the endogenous cannabinoid anandamide plays an important role in a cannabinergic pain-suppression system existing within the dorsal and lateral PAG. The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.

Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation.

Localization of cannabinoid CB 1 receptors on GABAergic interneurons in the rat hippocampal formation was studied by double-labeling immunohistochemistry with confocal microscopy. Virtually all CB1-immunoreactive neurons (95%) are GABAergic. CB 1 fluorescence showed a punctate pattern. In contrast, the GABA fluorescence was distributed homogeneously, suggesting that while CB 1 receptors and GABA exist in the same cells they are not localized in the same subcellular compartments. Although virtually all CB1 neurons were GABAergic, many GABAergic neurons did not contain CB1 receptors. GABAergic interneurons in the hippocampal formation can be further divided into subpopulations with distinct connections and functions, using cell markers such as neuropeptides and calcium binding proteins. CB1 receptors were highly co-localized with cholecystokinin and partially co-localized with calretinin and calbindin, but not with parvalbumin. This suggests that cannabinoids may modulate GABAergic neurotransmission at the synapses on the soma and at synapses on the proximal dendrites of the principal neurons, as well as at synapses on other GABAergic interneurons.

3-D power Doppler cerebral angiography in neonates and young infants: comparison with 2-D power Doppler angiography.

The aims of this study were to evaluate the ability of 3-dimensional (3-D) power Doppler angiography (3DPDA) to depict the intracranial vasculature in infants, to compare with 2-D power Doppler ultrasonography (2DPDU), and to explore the potential clinical applications of this procedure in young infants with brain disorders. We performed 3DPDA in 27 infants. 2DPDU were completed in both sagittal and coronal directions in 12 of these patients. In the other 15, only right sagittal plane images were available for comparison. Using a grading system and with only vessels with more than half of the length demonstrated included for comparison, we compared the Doppler signals of major vessels. 3DPDA could have good visualization in more than 60% of the internal carotid artery, ophthalmic artery, pericallosal artery, callosomarginal artery, internal cerebral vein, vein of Galen, and straight sinus in the sagittal plane. 3DPDA also could have good demonstration in about 50% of basilar artery in coronal plane, and posterior communicating artery, posterior cerebral artery, and lenticulostriate artery in sagittal plane. 3DPDA was better than 2DPDU in demonstrating all the major intracranial vessels in different planes, except the anterior communicating artery. In the anterior communicating artery, neither can demonstrate more than 30%.

The neurobiology of cannabinoid analgesia.

The discovery of cannabinoid receptors and their putative endogenous ligands raises questions as to the nature of the effects produced by cannabinoids on neural circuits that mediate pain and whether endogenous cannabinoids produced by the brain or in the periphery serve naturally to modulate pain. A sizable body of previous work showed that cannabinoid agonists suppress pain behavior in a variety of models of acute and chronic pain. However, at appropriate doses, cannabinoids also profoundly suppress motor behavior (see Sañudo-Peña et al., this volume), which complicates the interpretation of behavioral analgesia since a motor response is the endpoint of virtually all such studies. Studies conducted in this laboratory used biochemical and neurophysiological measures to determine whether cannabinoids suppress nociceptive neurotransmission. The results showed that cannabinoids suppress nociceptive neurotransmission at the level of the spinal cord and the thalamus. These effects are reversible, receptor mediated, selective for painful as opposed to nonpainful somatic stimuli, and track the behavioral analgesia both in time course and potency.

Motor actions of cannabinoids in the basal ganglia output nuclei.

The levels of CB1 cannabinoid receptors in the basal ganglia are the highest in the brain, comparable to the levels of dopamine receptors, a major transmitter in the basal ganglia. This localization of receptors is consistent with the profound effects on motor function exerted by cannabinoids. The output nuclei of the basal ganglia, the globus pallidus (GP) and substantia nigra reticulata (SNr), apparently lack intrinsic cannabinoid receptors. Rather, the receptors are located on afferent terminals, the striatum being the major source. Cannabinoids blocked the inhibitory action of the striatal input in the SNr. Furthermore, cannabinoids blocked the excitatory effect of stimulation of the subthalamic input to the SNr revealing, along with data from in situ hybridization studies, that this input is another likely source of cannabinoid receptors to the SNr. Similar actions of cannabinoids were observed in the GP. Behavioral studies further revealed that the action of cannabinoids differs depending upon which input to the output nuclei of the basal ganglia is active. The inhibitory striatal input is quiescent and the cannabinoid action is observable only upon stimulation of the striatum, while the noticeable effect of cannabinoids under basal conditions would be on the tonically active subthalamic input. These data suggest that the recently discovered endogenous cannabinergic system exerts a major modulatory action in the basal ganglia by its ability to block both the major excitatory and inhibitory inputs to the SNr and GP.

Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections.

Cannabinoids suppress behavioral and neurophysiological responses to noxious stimuli in rodents when administered systemically. The purpose of this study was to extend previous studies of the site of cannabinoid analgesia. Rats were tested in the tail flick test before and after microinjections of the cannabinoid agonist WIN55, 212-2 (5 microg) into one of 17 different brain regions. WIN55,212-2 significantly elevated tail-flick latencies when injected into the amygdala, the lateral posterior and submedius regions of the thalamus, the superior colliculus and the noradrenergic A5 region. By contrast, pain behavior was unaffected by microinjections of the cannabinoid into the other 11 areas examined (prefrontal cortex, nucleus accumbens, lateral hypothalamus, substantia nigra, cuneiform nucleus, anterior pretectal, intralaminar, parafasicular, posterior, thalamic nuclei, as well as the ventral medial, ventral lateral nuclei in the posterior thalamus).

Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat.

The effects of cannabinoid agonists on noxious heat-evoked firing of 62 spinal wide dynamic range (WDR) neurons were examined in urethan-anesthetized rats (1 cell/animal). Noxious thermal stimulation was applied with a Peltier device to the receptive fields in the ipsilateral hindpaw of isolated WDR neurons. To assess the site of action, cannabinoids were administered systemically in intact and spinally transected rats and intraventricularly. Both the aminoalkylindole cannabinoid WIN55,212-2 (125 microg/kg iv) and the bicyclic cannabinoid CP55,940 (125 microg/kg iv) suppressed noxious heat-evoked activity. Responses evoked by mild pressure in nonnociceptive neurons were not altered by CP55,940 (125 microg/kg iv), consistent with previous observations with another cannabinoid agonist, WIN55,212-2. The cannabinoid induced-suppression of noxious heat-evoked activity was blocked by pretreatment with SR141716A (1 mg/kg iv), a competitive antagonist for central cannabinoid CB1 receptors. By contrast, intravenous administration of either vehicle or the receptor-inactive enantiomer WIN55,212-3 (125 microg/kg) failed to alter noxious heat-evoked activity. The suppression of noxious heat-evoked activity induced by WIN55,212-2 in the lumbar dorsal horn of intact animals was markedly attenuated in spinal rats. Moreover, intraventricular administration of WIN55,212-2 suppressed noxious heat-evoked activity in spinal WDR neurons. By contrast, both vehicle and enantiomer were inactive. These findings suggest that cannabinoids selectively modulate the activity of nociceptive neurons in the spinal dorsal horn by actions at CB1 receptors. This modulation represents a suppression of pain neurotransmission because the inhibitory effects are selective for pain-sensitive neurons and are observed with different modalities of noxious stimulation. The data also provide converging lines of evidence for a role for descending antinociceptive mechanisms in cannabinoid modulation of spinal nociceptive processing.

CB1 receptor localization in rat spinal cord and roots, dorsal root ganglion, and peripheral nerve.

AIM: The localization of CB1 receptors in the spinal cord, spinal roots, dorsal root ganglion (DRG), and peripheral nerve of the rat was determined. METHODS: We studied the distribution of CB1 cannabinoid receptors by immunohistochemistry using an antibody raised against the N-terminal of the receptor. RESULTS: The spinal cord showed numerous transverse fibers labelled for CB1 receptors throughout and concentrated in the dorsal horn. Lightly-stained cells were observed throughout the spinal cord gray matter. The DRG also showed cells and fibers labelled for CB1 receptors. Labelled fibers were observed in both dorsal and ventral roots as well as in peripheral nerves. CONCLUSION: The presence of CB1 receptors in the DRG, the dorsal root, and the dorsal horn is in accordance with the analgesic effects of cannabinoids. The presence of labelled cells and fibers in the ventral horn and ventral root provides a substrate for cannabinoid-induced muscle relaxant and antispastic effects.

Intrathecal cannabinoid administration suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in rat spinal cord: comparison with morphine.

AIM: To determine whether cannabinoids suppress noxious stimulus-evoked Fos protein-like immunoreactivity (FLI) through direct actions at the spinal level. METHODS: Rats were implanted with intrathecal (ith) catheters at least one week prior to evaluation in the formalin test. Effects of the cannabinoid agonist, CP55,940 (80 micrograms ith) on formalin pain and FLI in rat spinal cord were compared with that of the prototypic narcotic analgesic, morphine (20 micrograms ith). CP55,940 suppressed pain behavior and FLI induced by intraplantar formalin. The cannabinoid suppressed Fos in the neck region of the dorsal horn and in the ventral horn, but not in the nucleus proprius. The efficacy of the cannabinoid in suppressing FLI in these laminae and pain behavior was comparable to morphine administered via the same route. However, only morphine suppressed FLI in the superficial dorsal horn relative to vehicle treatment. CONCLUSION: Cannabinoids suppress nociceptive processing, in part, through actions at the spinal level. However, morphine showed greater potency and efficacy than CP55,940 in suppressing formalin-induced FLI following spinal administration.

Dopaminergic system does not play a major role in the precipitated cannabinoid withdrawal syndrome.

AIM: To determine the dopaminergic system involvement in precipitated cannabinoid withdrawal syndrome. METHODS: The dopamine D1 receptor antagonist SCH23390 or the dopamine D2 receptor antagonist sulpiride was administered to rats chronically treated with either delta 9-tetrahydrocannabinol (THC) or vehicle. Subjects were then injected with either SR141716A or vehicle and behavior was observed for 1 h. RESULTS: Administration of the cannabinoid receptor antagonist SR141716A to animals chronically treated with THC as described by Tsou et al (1995) produced a profound withdrawal syndrome. Treatment with dopamine antagonists did not attenuate cannabinoid precipitated withdrawal syndrome in THC tolerant animals while the agonists increased the syndrome. CONCLUSION: It is unlikely that the dopaminergic system plays a major role in mediating the behavioral aspects of the cannabinoid withdrawal syndrome.

Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212-2.

The effects of spinally administered cannabinoids on nociceptive responses of wide dynamic range (WDR) neurons in the lumbar spinal cord were investigated in urethane-anesthetized rats. Noxious thermal stimulation was applied with a Peltier device to regions of the ipsilateral hindpaw corresponding to the receptive fields of isolated neurons. WIN55,212-2 (100 microg, i.t.), applied topically on the dorsal spinal surface, suppressed noxious heat-evoked activity in spinal WDR neurons. By contrast, responsiveness was unchanged following administration of either vehicle or WIN55,212-3, the receptor-inactive enantiomer. WIN55,212-2, administered intrathecally to separate rats, produced antinociceptive effects in the tail-flick test with a time course and efficacy that paralleled the suppression of noxious heat-evoked activity. These results suggest that cannabinoid modulation of spinal nociceptive processing involves direct actions in the spinal dorsal horn and is related to the antinociceptive effects of intrathecally administered cannabinoids.

Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity.

The competitive CB1 receptor antagonist SR141716A was used to test the hypothesis that endogenous cannabinoids modulate tonic pain sensitivity. Pretreatment with the antagonist significantly enhanced the response to a chemical nociceptive stimulus in the formalin test. Postreatment with the antagonist 5 min following the induction of tonic pain produced hyperalgesia during the tonic phase only. These findings suggest that endogenous cannabinoids serve naturally to modulate the maintenance of pain following repeated noxious stimulation.

Effects of intrastriatal cannabinoids on rotational behavior in rats: interactions with the dopaminergic system.

The effect of unilateral intrastriatal cannabinoid receptor stimulation on rotational behavior in rats was explored. The potent cannabinoid agonist CP 55,940 (5 microg/0.5 microl) induced contralateral turning when microinjected unilaterally into the striatum. The D2 dopamine agonist quinpirole reversed this contralateral rotation but failed to affect motor behavior on its own. Finally, the D1 dopamine agonist SKF 82958 inhibited movement when administered into the striatum and this inhibition was reversed by co-administration of the cannabinoid agonist. Surprisingly, microinjections of the cannabinoid agonist into the striatum induced movement through activation of the striatonigral pathway and/or inhibition of the striatopallidal pathway, while the D1 dopamine agonist produced the opposite effect.

Cannabinoid effects in basal ganglia in a rat model of Parkinson's disease.

Cannabinoid receptors in the brain are highly concentrated in the basal ganglia, which is in accordance with their well known effects on motor behavior. In this study, rats with 6-hydroxydopamine lesions of the nigrostriatal pathway were implanted with cannulae in the striatum, globus pallidus and substantia nigra. The effect of unilateral infusion of the potent cannabinoid agonist CP55,940 on turning behavior was studied for each structure. Lesioned animals responded to intrapallidal and intrastriatal administration of the cannabinoid in a manner that was similar to that of unlesioned animals. However, lesioned animals showed greater contralateral turning in response to the cannabinoid infusions in the substantia nigra than unlesioned animals.

Long QT syndrome manifested as fetal ventricular tachycardia and intermittent AV block.

A case of long QT syndrome diagnosed in the early neonatal period is described. This full-term female baby had intermittent atrioventricular (AV) block and ventricular tachycardia detected antenatally at the gestational age of 26 weeks. Sinus rhythm with prolonged QT interval (QTc = 0.636 sec) was found soon after birth. She developed variable degree of AV block with alternating left and right bundle branch block, which suggested the presence of multilevel AV block. Her mother had no lupus autoantibodies. Auditory brain stem evoked potential was normal. Family study revealed QT prolongation in her grandmother. Her condition improved after pacemaker implantation and oral beta-blocker usage.