Olanzapine: a basic science update

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype: and alpha 1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5-HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas of the brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.     

Clinical nutrition in danish hospitals: a questionnaire-based investigation among doctors and nurses.

Specific nutrition standards are now developed by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in order to improve the nutritional status in hospitalized patients. We investigated the use of clinical nutrition in Danish hospitals and compared it with the standards of JCAHO by doing a questionnaire-based investigation among doctors and nurses randomly selected in 40 hospitals including internal medicine, gastroenterology, oncology, orthopedic departments and intensive care units (ICU).Overall, 857 (43.4%) responded to the questionnaire (doctors: 395, nurses: 462). Seventy-seven percent stated that nutritional assessment ought to be performed on admission, but only 24% stated that it was a routine procedure. Forty percent found it difficult to identify risk-patients, and 52% needed specific screening tools. Twenty-two percent registered body weight in all patients, and 18% registered nutrient intake routinely. Eighty-four percent found that a nutrition plan should be described in the patient record, but 39% found it difficult to set up an individual plan, and 79% expressed a need for specific guidelines. Eighty-four percent would only accept a patient being on isotonic glucose and/or electrolyte infusion for < 5 days (42% for < 2 days), and 33% would only accept a weight loss of 5% before active nutrition was initiated. About 50% would be restrictive in supplying enteral or parenteral nutrition to patients with impaired liver or kidney function. Twenty-seven percent did not use active nutritional therapy at all. Seventy-six percent found that nutritional assessment should be performed during hospital stays, but only 23% monitored the nutritional status. Sixty-eight percent stated that responsibility should be assigned to one or more persons, but this was the case in only 20%The use of clinical nutrition in Danish hospitals did not fulfill the standards for nutrition support according to the criteria established by JCAHO. Special efforts should be aimed at education, specific screening tools and introduction of guidelines in clinical nutrition.     

A history of placental dysfunction and risk of placental abruption

In a population-based historic cohort study, we assessed the possible association of fetal growth retardation, preterm birth and pregnancy-induced hypertension in the immediately preceding pregnancy with placental abruption in the current pregnancy, which would suggest a shared aetiological factor. We also assessed whether chronic hypertension, diabetes mellitus and a history of Caesarean section are associated with placental abruption. Preterm birth and small-for-gestational-age (SGA) in the immediately preceding delivery were associated with an increased risk of placental abruption with unadjusted odds ratios (ORs) of 2.1 [95% CI = 1.9, 2.4] and 1.6 [95% CI = 1.5, 1.8] respectively. Women with a history of an SGA preterm birth in the immediately preceding delivery and an appropriate-for-gestational-age infant in the current had an adjusted OR of 3.2 [95% CI = 2.3, 4.5]. The adjusted odds ratio of placental abruption in women who had pregnancy-induced hypertension in the previous pregnancy, but not in the current, was 1.4 [95% CI = 1.2, 1.7]. Women who delivered a preterm or SGA infant in the previous delivery and had chronic hypertension or diabetes mellitus in the current had adjusted ORs of 2.3–5.7 and 2.5–6.0 respectively. Caesarean section in the previous delivery increased the risk of placental abruption by 40%. These results suggest that pregnancy-induced hypertension, intrauterine growth retardation, preterm delivery and placental abruption share an aetiological factor or represent different clinical expressions of recurring placental dysfunction. Chronic hypertension and diabetes mellitus may cause or aggravate such dysfunction thus causing placental abruption. A history of Caesarean section is associated with an increased risk of placental abruption.     

Automatic Border Detection to Assess Right Ventricular Function Following Surgical Treatment of Thromboembolic Pulmonary Hypertension

Automatic border detection (ABD) has been developed as a potentially useful means for evaluating ventricular function on line in an automatic fashion. Its success with tracking left ventricular function is established, but little is known about its ability to assess right ventricular (RV) function. Accordingly, 20 patients with severe pulmonary hypertension due to chronic thromboembolic disease underwent standard two-dimensional echocardiography and imaging with ABD before and after pulmonary thromboendarterectomy to correct pulmonary hypertension. ABD-derived results were compared to manually planimetered RV areas calculated from the apical four-chamber view. Doppler tricuspid regurgitant velocity fell significantly with surgery from 4.4 ± 0.6 to 2.9 ± 0.7 m / sec (P < 0.001). The mean values for RV areas derived by manual planimetry and ABD were similar, as was fractional area shortening, which improved significantly with surgery (manual 0.24 ± 0.01 preoperative vs 0.31 ± 0.11 postoperative, P < 0.05; and ABD 0.19 ± 0.05 preoperative vs 0.32 ± 0.15 postoperative, P < 0.001). There was, however, very little correlation between the individual values for ABD versus manually derived RV areas and fractional area shortening, with the best correlation being the RV end-diastolic areas after surgery (y = 0.684x + 7.9, r = 0.564, P = 0.01). These results demonstrate that both manually planimetered RV areas and those determined by ABD can adequately follow changes in ventricular function over time. However, variability within each technique may prevent direct comparison of the absolute values of the two techniques.     

Beta-oxidation of 1-[14C]-17-[131I]-iodoheptadecanoic acid following intracoronary injection in humans results in similar release of both tracers

Radioiodine labelled 17-iodo-heptadecanoic acid (IHA) is used for non-invasive study of myocardial metabolism in coronary heart disease and cardiomyopathy. Yet in the interpretation of in vivo myocardial tracer kinetics, it is controversial whether the intracellular degradation of IHA or the removal of iodide across cellular membranes is the rate-limiting step in iodide release from the myocardium. In five patients undergoing coronary sinus catheterization, a mixture of about 40 kBq of [¹²³I] NaI was injected into the left coronary artery. During the following 15-min period, frequent blood samples were taken from the aorta and the coronary sinus. In the aqueous phase of the venous blood, ¹⁴CO₂ and inorganic ¹³¹I appeared nearly in parallel, with a peak time of 4–5 min. Moreover, as shown by the AV difference, there was no significant back diffusion of IHA and no significant non-specific deiodination detectable over the period of observation. There was myocardial retention of inorganic iodide (¹²³I) injected into the left coronary artery. The data strongly support the premise that lipid turnover through -oxidation is the rate-limiting step in the externally measured release of iodide after IHA injection, provided that recirculating inorganic radioactive iodide is corrected for. In addition, 15 volunteers were studied using [¹¹C]palmitic acid and [¹²³I]IHA using PET and dynamic planar camera scintigraphy with iodide correction. There was no significant difference between the mean values of the elimination half-times, and also no significant correlation between half-times of both fatty acids for single individuals.     

Prodrugs of Peptides. 9. Bioreversible N-α-Hydroxyalkylation of the Peptide Bond to Effect Protection Against Carboxypeptidase or Other Proteolytic Enzymes

Various N--hydroxyalkyl derivatives of N-acyl amino acids and di- and tripeptides were prepared by hydrolysis or aminolysis of N-acyl 5-oxazolidinones. The stability of these derivatives was studied in aqueous solution as a function of pH. The compounds were all degraded quantitatively to their parent N-acylated amino acid or peptide and aldehyde but with vastly different rates. At pH 7.4 and 37°C the half-lives of decomposition ranged from 4 min to 1500 hr. The structural factors influencing the stability included both steric and polar effects within the acyl and N--hydroxyalkyl moieties as well as within the amino acid attached to the N--hydroxyalkylated N-acyl amino acid. Whereas the N-benzyloxycarbonyl (Z) derivatives of the dipeptides Gly-L-Leu and Gly-L-Ala were readily hydrolyzed by carboxypeptidase A, the N-hydroxymethylated compounds, i.e., Z-Gly(CH₂OH)-Leu and Z-Gly(CH₂OH)-Ala, were resistant to cleavage by the enzyme as revealed by their similar rates of decomposition in the presence or absence of the enzyme at pH 7.4 and 37°C. The results suggest that N--hydroxyalkylation of a peptide bond protects not only this bond but also an adjacent peptide bond against proteolytic cleavage. Since the N--hydroxyalkyl derivatives are readily bioreversible, undergoing spontaneous hydrolysis at physiological pH, this prodrug approach promises to overcome the enzymatic barrier to absorption of various peptides.     

Facial pain

Summary In a prospective material of 1052 patients the precipitating factors, associated symptoms, psychological and neurological deficits have been examined.Mastication and talking are the most frequently occurring precipitating factors, 76% as regards Neuralgia, with typical starting difficulties. As regards Non-neuralgiform Pain 24%, with precipitation late in the masticatory process. There were trigger zones in 50% of the cases of Typical Trigeminal Neuralgia and in 9% of the patients with Non-neuralgiform Pain. In a series of cases the jaw joint is perceived as a trigger zone. Cold precipitates pain in 48%–39%. Other precipitating factors are much more rare-psychological stress in 15% of the patients with Non-neuralgiform Pain, however.Vegetative associated symptoms were relatively frequent, lacrimation occurred in 31% of the cases of Typical Trigeminal Neuralgia and in 20% of the cases of Non-neuralgiform Pain. Rhinorrhea and salivation were less frequent. In terms of figures migrainoid associated symptoms had no connection with vegetative associated symptoms or with pain in the eye.In 11 % of the patients pain occurred most frequently during the night and in 20% the frequency of pain was the same day and night. About 1/3 of the patients with Neuralgia experienced seasonal variations.Tenderness of foramina is a symptom of no significance. Very few patients had primary sensory loss. No eye or ear symptoms have been found which may be referred to as the patho-anatomical basis of the pain.About 1/3 of the patients with Non-neuralgiform Pain had psychological symptoms whereas hardly any patients with Neuralgia had them. MMPI test performed on a small matched material showed no difference between Neuralgia and Non-neuralgiform Pain.In material B an examination has been made of the jaw joint arthrosis symptoms. A restriction of the diagnosis of arthrosis has had the effect that it must be recognized that patients with facial pain do not have the high frequency of jaw joint diseases previously assumed. As was also the case in a series of normal material previously published, between 1/5 and 1/3 of the patients with Neuralgia had jaw joint arthrosis which was due to old age.This study has not revealed any connection between previous diseases, the onset of pain, the character and course of the pain, the character of the attack, the localization of pain, precipitating factors, associated symptoms and symptoms of loss on the one hand and the patho-anatomical substratum on the other.The psychological examinations were performed by Mr. Peter Bruun, chief psychologist, for whose cooperation I am grateful.     

Muscle mass effect on arterial desaturation after maximal exercise.

We measured arterial oxygen saturation before and immediately after randomly allocated 6 min of "all-out" maximal arm cranking, treadmill running, and ergometer rowing in 10 men and women with a median maximal oxygen uptake of 4.47 (range 3.22-5.34) 1.min-1. Arterial saturation for oxygen was unaltered after arm cranking, but decreased 1.7 (-2.5-6.0) % (P less than 0.05) after running, and 2.2 (1.0-8.7) % (P less than 0.01) after rowing. Arterial saturation was inversely related to capillary blood lactate, which reached 11.8 (7.4-14.0), 12.6 (8.9-18 2), and 14.3 (12.0-19.3) mmol.l-1 (P less than 0.01), respectively, and arterial bicarbonate fell to 15.0 (13.0-23.6), 12.4 (7.2-20.4), and 10.8 (0.0-12.5) mmol.l-1 (P less than 0.01). Thus, pH decreased to 7.25 (7.22-7.40), 7.17 (6.95-7.35), and 7.09 (6.84-7.19) (P less than 0.01). When measured immediately post-exercise, arterial oxygen tension was unchanged or elevated from rest, eliminating the possibility that the arterial desaturation was caused by a pulmonary diffusion limitation. The results of this investigation show that arterial desaturation associated with maximal exercise takes place in proportion to the involved muscle mass, as do deviations in blood lactate, bicarbonate, and hydrogen concentrations.     

Effect of acetylsalicylic acid on renal function in systemic lupus erythematosus

Summary Glomerular filtration rate (GFR;⁵¹Cr-EDTA clearance), serum creatinine concentration and urinary excretion of prostaglandins were measured in 8 patients with systemic lupus erythematosus (SLE) before and after 2 weeks of treatment with acetylsalicylic acid (ASA). ASA 65 mg/kg or up to 4 g/daily was given as a sustained release preparation. The serum salicylate concentration ranged from 0.3 to 1.6 mmol/l. Serum creatinine after 1 and 2 weeks and GFR after 2 weeks of ASA treatment showed no significant changes. There was a clearcut decrease in urinary excretion of prostaglandins PGE₂ and PGF₂, by 44% and 50%, respectively. It is concluded that therapeutic doses of ASA do not cause deterioration of GFR in patients with SLE and normal or moderately reduced renal function.