Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes.

AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals.

Relationship of monoamine oxidase A binding to adaptive and maladaptive personality traits.

BACKGROUND: Monoamine oxidase A (MAOA) is an important enzyme that metabolizes monoamines such as serotonin, norepinephrine and dopamine in the brain. In prefrontal cortex, low MAOA binding is associated with aggression and high binding is associated with major depressive disorder (MDD) and also risk for recurrence of depressive episodes. In rodent models, low MAOA levels are associated with increased aggression and fear conditioning, and decreased social and exploratory investigative behaviors. Our objective was to measure MAOA binding in prefrontal cortex and concurrently evaluate a broad range of validated personality traits. We hypothesized that prefrontal MAOA binding would correlate negatively with angry-hostility, a trait related to aggression/anger, and positively with traits intuitively related to adaptive investigative behavior. METHOD: Participants were aged 19-49 years, healthy and non-smoking. MAOA binding was measured with [11C]harmine positron emission tomography (PET) in prefrontal brain regions and personality traits were measured with the NEO Personality Inventory Revised (NEO PI-R). RESULTS: Prefrontal MAOA binding correlated negatively with angry-hostility (r=-0.515, p=0.001) and positively with deliberation (r=0.514, p=0.001). In a two-factor regression model, these facets explained 38% of variance in prefrontal MAOA binding. A similar relationship was found in prefrontal cortex subregions. CONCLUSIONS: We propose a new continuum describing the relationship between personality and MAOA: deliberate/thoughtful contrasting aggressive/impulsive. Additionally, the association between high MAOA binding and greater deliberation may explain why some people have moderately high levels of MAOA, although very high levels occur during MDD. In health, higher MAOA binding is associated with an adaptive personality facet.

Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus.

This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 +/- 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq (99m)Tc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq (67)Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a gamma camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response.

Postcibal gastric emptying of pancreatin pellets: effects of dose and meal oil.

To treat pancreatic exocrine insufficiency, physicians often prescribe enterically coated pellets of pancreatin to be taken with meals. The pellets are only partially effective in correcting the digestion and absorption of fat. We sought to determine in normal subjects whether emptying of pellets from the postcibal stomach was dose-related and whether the gastric emptying of lipophilic Creon-20 or Pancrease was altered by the presence or the absence of oil in a meal. Gastric emptying of pellets surface-labeled with 113mIn or 99mTc was followed with a gamma camera for 300 min after isocaloric meals. From our observations, we concluded that gastric emptying of 0.28-1.12 g of 1-mm or 2-mm pellets was dose-related (P < 0.01) and emptying of neither Creon-20 nor Pancrease was much affected by oil in the meal.

Increased left posterior parietal-temporal cortex activation after D-fenfluramine in women with panic disorder.

It is unclear whether the functional changes found in panic disorder reflect disturbed physiology of particular neurotransmitters. One method of investigating altered neurotransmission is to assess regional brain activations in response to agonist challenges. D-Fenfluramine is a medication that induces neuronal release of serotonin. Using ¿15OH(2)O and positron emission tomography (PET), measurements of regional cerebral blood flow (rCBF) were done at t=-20, -5, +20 and +35 relative to the IV D-fenfluramine injection (t=0) in nine panic-disordered and 18 healthy subjects. Subjects were otherwise healthy, right-handed, non-smoking and not taking psychotropic medication. ¿15OH(2)O PET scans were assessed with Statistical Parametric Mapping using individual global cerebral blood flow as a covariate. Comparisons of the (baseline) first two scans between healthy and panic-disordered subjects showed a decreased rCBF in the left posterior parietal-superior temporal cortex in the patient group. Fenfluramine-induced increases as defined by the last two scans minus the first two scans were compared between groups and a significantly greater increase in the same left posterior parietal-superior temporal region was found in panic-disordered subjects. Consistent with this finding, differences between the last two scans (post-fenfluramine) of the healthy and panic-disordered subjects showed an increased rCBF in the left superior temporal cortex in panic-disordered subjects. Functional pathology in the left parietal-superior temporal cortex in panic disorder may be related to abnormal modulation by serotonin.

Role of small intestine in caloric compensations to oil premeals in rats.

We postulated that dose-responsive satiety after oil premeals varies with the number of gut sensors stimulated by lipolytic products along intestine. These experiments in fasted rats on satiety after oil premeals were performed to 1) determine whether satiety was induced by lipolytic products but not triglycerides; 2) confirm that oil empties from the stomach at rates that vary with oil loads; 3) ascertain that increasing rates of oil entry into duodenum extend the length of gut contacted by lipolytic products; and 4) judge whether length of gut contacted correlated with dose-responsive satieties to dietary oils. 5) Using specific antagonists, we attempted to define how satiety was signalled by gut sensors. Timing and degrees of satiety did not correlate with timing and extent of gastric distensions but, rather, with the timing and extent of spread of lipolytic products along small bowel. Satiety after the highest premeal load of oil was blocked by Pluronic L-81, an inhibitor of intestinal secretion of apolipoprotein A-IV, but was unaffected by MK-329 (a specific antagonist of cholecystokinin) or by capsaicin blockade of chemosensory nerves.

Effect of aclacinomycin A on in vitro cultures of porcine lens epithelial cells.

As a potential drug for the prevention of secondary cataract formation (SCF), we investigated the effect of Aclacinomycin A (ACM) on the growth of cultures of porcine lens epithelial cells in vitro. ACM is an anthracycline that has been used in the treatment of acute myeloid leukemia in the human for many years. It has been shown to be non-mutagenic and non-carcinogenic in in vitro and in animal models. Subconfluent cell cultures were exposed to different concentrations of ACM for 5 minutes. The drug effect was evaluated by cell counts after various lengths of culture time (between 1 and 10 weeks). No cells survived the treatment with 12 or 16 microg ml-1. Cultures treated with concentrations between 0.5 and 8 microg ml-1 showed a marked decrease in cell number when compared to controls. However, reproliferation occurred at concentration up to 8 microg ml-1 after 2-6 weeks. Intraocular application of ACM might be suitable in the prevention of SCF. However, with regard to reproliferation, long-term cultures (or long-term animal models, respectively) have to be used in further evaluating the appropriate dosage for this purpose.

Mismatch of duodenal deliveries of dietary fat and pancreatin from enterically coated microspheres.

Gastric emptying of dietary fat is affected by both chemical and physical factors; but when ingested as a free oil or an aqueous emulsion, fat may empty most rapidly immediately after the meal. In contrast, gastric transit of 1- to 3-mm spheres (like those of enterically coated pancreatins) is known to vary inversely with sphere diameter; and spheres leave the stomach initially slowly, if their diameter is > or = 1.6 mm. Our objective was to determine whether 2-mm microspheres of Pancrease would empty much more slowly than free or emulsified oil and whether 1.2-mm microspheres of Creon would empty as fast as free oil. We used a gamma camera to track the concurrent gastric emptying of 123I-labeled oil and 113mIn-labeled spheres of Pancrease or Creon in pancreatic-insufficient subjects with cystic fibrosis who ingested 20 g of free oil in spaghetti meals or 20 g of oil emulsified in a milk meal. We found that either type of oil emptied rapidly initially but slowed later, whereas either dosage form emptied slowly initially but rapidly later. Unexpectedly, the smaller spheres of Creon emptied about the same as Pancrease did after the spaghetti meal. For example, 50% of oil but < 25% of either dosage form had left the stomach by 90 min after the meals. Both dosage forms were lipophilic, forming aggregates in vitro. We concluded that the gastric emptying of either dosage form frequently lagged behind the emptying of oil from ordinary meals. We speculated that the similar transits of the 1.2-mm Creon and the 2-mm Pancrease resulted from aggregation of these microspheres in the presence of free oil.

[How successful is the filtering bleb "needling"?]. / Wie erfolgreich ist das Sickerkissen-"Needling"?

BACKGROUND: "Needling" may become necessary when filtering blebs fail due to scarring or encapsulation. Our goal was to calculate the medium term success rate of the needling procedure. METHODS: The results of 90 needling procedures performed on 58 eyes were analyzed, 52 eyes required one single needling (group 1) after simple trabeculectomy, whereas 19 eyes had to have double needling (group 2) and 3 eyes had to be needled 3 times (group 3). These figures do not include a 4th group of 16 eyes which had been needled after repeated and complicated surgery. Success rates were calculated at t1 = 0 - 1 day, t2 = 1 - 4 weeks, t3 = 4 - 8 weeks, t4 = 3 - 5 months and t5 = > 6 months after the treatment. RESULTS: The mean IOP (n = 90) was 29 +/- 6 mm Hg preoperatively, 15 +/- 10 mm Hg at t1, 23 +/- 9 mm Hg at t2, 20 +/- 7 mm Hg at t3, 17 +/- 5 at t4 and 17 +/- 3 at t5. The overall success rates were 80% (t1), 45% (t2), 37% (t3), 35% (t4) and 31% (t5). The corresponding success rates were 74%, 36%, 32%, 28% and 26% for group 1.89%, 52%, 37%, 37% and 31% for group 2.67% at all times for group 3 and 100%, 69%, 54%, 54% and 45% for group 4. CONCLUSIONS: In one third of all cases the needling is effective for more than 6 months. A complicated pressure lowering surgery does not necessarily diminish the effectiveness of a needling procedure. Re-needlings are as successful as the first one.

[Success and complications of rTPA treatment of the anterior eye segment]. / Erfolge und Komplikationen der rTPA-Behandlung am vorderen Augenabschnitt.

Recombinant tissue plasminogen activator (rTPA) is commonly used in patients with myocardial infarction. Recently, it has also been applied intraocularly to dissolve postoperative fibrin with no serious complications being reported so far. In this study we describe our own experience with rTPA in 25 patients with persisting fibrinous membranes in the anterior segment. rTPA (Actilyse, Dr. Karl Thomae GmbH) was given in a single dose of 25 micrograms and injected into the anterior chamber via a paracentesis. We did not encounter any complications during the injection of rTPA. In 21 eyes fibrin could be reduced significantly, albeit sometimes only slowly. In 13 patients, the membrane had dissolved almost completely by the following day. In contrast, no success was observed after glaucoma surgery (2 eyes) and in chronic iritis (1 eye), or when fibrin mixed with blood was treated (1 eye). There were two (controllable) post-operative hemorrhages (rTPA after vitrectomy, and for fibrin/blood after cataract surgery). In addition, we noted 2 cases of irreversible superficial corneal clouding (rTPA after cataract surgery). We conclude that injection of rTPA can be a useful addition to steroid treatment in selective cases of persisting fibrin in the anterior segment. Long-standing membranes, however, are unlikely to be dissolved. Care should also be taken and rTPA be avoided when there is evidence of recent bleeding. Most worrying to us were the corneal complications that we cannot explain to date. With regard to the definite time correlation we feel that rTPA or one of the solution components might be the cause of this unusual feature.

Twenty four hour blood pressure monitoring in normal tension glaucoma.

BACKGROUND: The few investigations that used continuous 24 hour blood pressure monitoring to investigate whether blood pressure in patients with normal tension glaucoma is lower than in normal subjects yielded conflicting results. Therefore, a prospective controlled trial was carried out. METHODS: Systemic blood pressure was recorded continuously over a 24 hour period in 20 patients with normal tension glaucoma (IOP < or = 21 mm Hg). Eight of them showed a localised loss of the neuroretinal rim area and, in addition, optic disc haemorrhages-that is, focal ischaemic signs. Twenty healthy patients without glaucoma, who were hospitalised for cataract or retinal surgery, served as controls. Blood pressure was automatically measured every 20 minutes during the day and every 40 minutes at night. RESULTS: Both groups showed a significant (physiological) blood pressure drop at night, which was significantly (p < 0.001, ANOVA) more pronounced in the group with normal tension glaucoma than in the control group. There was a weak trend towards lower blood pressure values in the normal tension glaucoma group. Minima, maxima, and mean values of the systolic, diastolic, and mean arterial pressures did not differ significantly between the group with normal tension glaucoma and the control group. The greatest differences occurred with nocturnal systolic and diurnal diastolic values. There were no significant differences between the subgroup with focal lesions and the other patients with normal tension glaucoma. CONCLUSIONS: Patients with normal tension glaucoma tend to have lower blood pressure values (p > 0.05, ANOVA) than normals; this difference is probably much smaller than formerly assumed. Patients with normal tension glaucoma, however, have significantly greater nocturnal blood pressure drops (p < 0.001, ANOVA) than normal controls. Nocturnal blood pressure drops (relative day-night differences) may play a more important role in the pathogenesis of normal tension glaucoma than the absolute height of the blood pressure.

Gastric emptying of oil from solid and liquid meals. Effect of human pancreatic insufficiency.

Digestion of fat in pancreatic insufficiency (PI) is strongly affected by how rapidly fat enters the duodenum. We postulated that: (1) oil empties faster in PI than in normals and (2) in both, it empties in a load-dependent fashion. We used a gamma camera to test these ideas by comparing gastric emptying of iodine-123 iodinated oil in normal and pancreatic-insufficient subjects after 15 g of free oil were ingested in a small spaghetti meal and 60 g of oil were ingested in a large spaghetti meal and in a milk emulsion. Indium-113m marked gastric emptying of water in the milk. In both groups after all meals, oil emptied fastest initially, slowing later; and oil emptied three to four times faster when 60 g vs 15 g were ingested. There were no significant differences between the groups of subjects with respect to gastric emptying of the spaghetti meals, but the pancreatic-insufficient subjects emptied both oil and water faster from the milk emulsion than did the normal subjects. The slower emptying of oil in the normal subjects was associated with significantly more layering of oil to the top of the intragastric milk emulsion.

A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin.

OBJECTIVE: To determine whether intravenously administered iron supplements would improve the hematologic response to recombinant erythropoietin in stable preterm infants. METHODS: Forty-two preterm infants (<33 weeks' gestation, birth weight < 1500 gm, hematocrit <38%) were treated with recombinant human erythropoietin (Eprex), 600 U/kg per week, and randomly assigned to receive either an oral preparation of ferrous lactate (elemental iron, 12 mg/kg per day) or an intravenous preparation of iron sucrose (6 mg/kg per week). RESULTS: Hematocrits, reticulocyte counts, and transfusions were similar in the oral group (OG) and the intravenous group (IVG). However, markedly higher serum ferritin concentrations were noted in the IVG (p <0.001), and by completion of the study the arithmetic mean values were 265 +/- 127 microg/L versus 137 +/- 65 microg/L in the IVG and the OG, respectively. The numbers of hypochromic erythrocytes increased in both groups during the study but were significantly higher in the OG (p = 0.04). Mean daily weight gain in the IVG (27 +/- 6.4 gm/day) was greater than in the OG (22.9 +/- 4.78 gm/day; p = 0.04). CONCLUSIONS: High doses of both orally administered iron and intravenously administered iron sucrose appear to supply sufficient iron for erythropoiesis in stable infants. Storage iron may become depleted after oral supplementation. The intravenous preparation appears to be safe and maintains serum ferritin concentrations, and it may be indicated for patients with low ferritin levels and for those not established on enteral feedings.

Midline granuloma presenting as orbital cellulitis.

BACKGROUND: Lethal midline granuloma usually presents with rhinorrhoea and redness of the skin above the nose. Early ocular symptoms are very rare. We here describe a patient who presented with acute orbital cellulitis. PATIENT: A 73-year-old woman had a 24-h history of severe pain around her left eye. We saw the typical clinical picture of orbital cellulitis. A CT scan revealed a diffuse infiltration of the left upper and lower lid, the anterior orbit and the ethmoidal sinuses. RESULT: On surgical exploration we found a granular, partly necrotic tumour. Histological examination revealed an angiocentric nasal T-cell lymphoma (midline granuloma). CONCLUSION: Midline granuloma should be included in the differential diagnosis of acute orbital cellulitis.

Gastric emptying of oil and aqueous meal components in pancreatic insufficiency: effects of posture and on appetite.

The aims of this study were to evaluate the effects of posture on gastric emptying, intragastric distribution, and satiation after a meal containing oil and aqueous phases in patients with exocrine pancreatic insufficiency. Five patients with cystic fibrosis (CF) consumed 60 ml 99mTc-labeled (V)-thiocyanate olive oil and 290 ml 113mIn-labeled diethylenetriaminepentaacetic acid soup while sitting and while lying in the left lateral decubitus position. Hunger and fullness before and after the meal were recorded. Results were compared with those obtained in 11 normal volunteers. In both postures emptying of oil was faster (P < 0.01) in CF patients. Emptying of the aqueous phase was faster (P < 0.01) in CF patients in the decubitus position. In normal subjects there was no overall difference in emptying of oil between the two postures, whereas emptying of the aqueous phase was delayed (P < 0.01) in the decubitus position. In CF patients emptying of oil was faster (P < 0.01) in the decubitus position, and emptying of the aqueous phase was only slightly faster (P < 0.05) in the sitting position. For both postures there was greater retention (P < 0.05) of oil in the proximal stomach in normal subjects than CF patients. Hunger decreased (P < 0.05) after the meal in the control subjects, but there was no change in CF patients. These results indicate that in CF patients with pancreatic exocrine insufficiency 1) gastric emptying of nonhomogenized fat is faster than normal, 2) gravity affects gastric emptying of oil, and 3) effects of a fatty meal on hunger are reduced.

[Results of cyclocryocoagulation]. / Ergebnisse der Zyklokryokoagulation.

BACKGROUND: The success of a cyclocryocogulation is not only defined by the reduction of the intraocular pressure but also by the simplification of the therapy necessary for the regulation of the glaucoma. PATIENTS: We examined retrospectively the charts of 27 patients with glaucoma chronicum simplex (GCS) and 63 patients with various types of non-simplex glaucomas (NGCS). All underwent a cyclocryocoagulation made 51 seconds at -70 to -80 degrees C, 4 mm behind the limbus at 6 points. RESULTS: IOP was controlled (i.e. < 25 mm Hg and decreased > 20% of the preoperative value) in 69% of the cases (GCS 70%, NGCS 68%) 3-5 days after the operation. IOP decreased from 31 to 19 mm Hg on average. The effect decreased with time, more than 12 months after the operation only 36% of the eyes were still regulated. 4 eyes with persisting pain had to be enucleated. The cyclocryocoagulation never caused blindness or phthisis bulbi. Therapy with eye drops was necessary in 70% of the patients preoperatively, and in 37% postoperatively. Oral carboanhydrase inhibitors had to be used in 57% of the patients before and in 20% of the cases after the operation. CONCLUSION: Cyclocryocoagulation is considered an effective method to lower IOP and simplify drug therapy without having serious complications.

Nutritional outcomes of gastric operations.

It is important to understand the digestive disturbances and nutritional outcomes of that may follow stomach resections. This article focuses primarily on the nutritional consequences of traditional gastric operations for ulcers, but related cancer and bariatric operations also are discussed.