REHABILITATION FOR STROKE SURVIVORS—A REVIEW

With the growing advent of rehabilitation units designed particularly for the needs of the stroke patient, a need has arisen for the evaluation of these units. In particular, several questions have to be asked     

A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pK_a value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α₁-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.     

Dextran sedimentation induces a difference in the percentage of hypodense eosinophils in peripheral blood between children with allergic asthma and healthy controls

Considerable differences in the percentage of hypodense eosinophils in the peripheral blood of asthmatics have been reported by different investigators. In these previous studies dextran sedimentation was used for removal of erythrocytes prior to density centrifugation. We hypothesized that the sedimentation procedure might induce the presence of hypodense eosinophils in the peripheral blood of asthmatic patients. In order to test this hypothesis, we compared eosinophil density profiles from peripheral blood of children with asthma and of age-matched healthy controls, using different procedures. In the first method (direct method) blood samples were directly layered on a discontinuous Percoll gradient. Erythrocytes were removed by isotonic lysis. In the second method (dextran sedimentation) erythrocytes were removed by sedimentation with dextran prior to gradient centrifugation. Results of the direct method show no significant difference in percentage of hypodense eosinophils between children with asthma and healthy controls (9.19% and 6.84% respectively). However, after dextran sedimentation, children with asthma had a significantly higher percentage of hypo-dense eosinophils than healthy controls (15.40% and 8.84% respectively; P < 0.05). The percentage of hypodense eosinophils was correlated with the number of eosinophils and with the lung function, measured as the Tiffeneau index (FEV₁/VC), in the whole group of subjects when the direct method was used. We conclude that an increased percentage of hypodense eosinophils is not present in the circulation of children with asthma, but can be induced in vitro by dextran sedimentation. Therefore, in vitro generation of hypodense eosinophils in the blood of patients with asthma seems to be related with the primed state of eosinophils.     

Inhibition of 3,3',4,4',5-Pentachlorobiphenyl-Induced Chicken Embryotoxicity by 2,2',4,4',5,5'-Hexachlorobiphenyl

3,3',4,4',5-Pentachlorobiphenyl (pentaCB) caused a dose-dependentinduction of chicken embryolethality, malformations, edema,and liver lesions at doses ranging from 0.5 to 12.0 µg/kg.In contrast, no embryotoxicity was observed after treatmentwith 10, 25, or 50 mg/kg 2,2',4,4',5,5'-hexaCB. In eggs cotreatedwith 2.0 µ/kg, 3,3',4,4',5-pentaCB plus 10, 25, or 50mg/kg 2,2',4,4',5,5'-hexaCB, there was significant protectionfrom 3,3',4,4',5-pentaCB-induced embryo malformations, edema,and liver lesions, whereas no inhibition of embryolethalitywas observed. These results further extend the response-specificnonadditive interactions of binary mixtures of polychlorinatedbiphenyls (PCBs) and should be considered in the developmentof approaches for hazard assessment of PCB mixtures and relatedcompounds.     

Immunotoxicological Profile of Morphine Sulfate in B6C3F1 Female Mice

This study was undertaken to investigate a number of immuneparameters which may be compromised with exposure to morphinesulfate. Mice were implanted subcutaneously with 8-, 25-, or75-mg morphine sulfate pellets. Placebo pellets of identicalmakeup to the 75-mg morphine pellet (without morphine of course)were used as a control. Twenty-four hours after implantationof a 75-mg morphine pellet, blood levels reached a peak of 1610ng/ml. Corticosterone increased in parallel with morphine andreached a peak level of 966 ng/ml 24 hr after implantation.The dose response of morphine to increase corticosterone, however,was fiat. The weight of the lymphoid organs, spleen and thymus,and the liver were significantly reduced in the morphine-treatedgroups. Morphine treatment was associated with an increase inserum albumin, SGPT, BUN, and alkaline phosphatase indicativeof hepatic damage. In contrast to increased serum proteins,the C3 component of complement was reduced in a dose-dependentmanner. Leukocyte number in the peripheral blood was significantlyreduced, while erythro-cyte number and hematocrit were bothincreased. The number of B cells and T cells was decreased inmorphine-treated animals. However, the percentage of T cellsrelative to B cells was increased. The primary IgM antibodyresponse to the T-depen-dent antigen, sheep red blood cells,was decreased. Natural killer cell activity was reduced in responseto morphine, as was the phagocytic capacity of Kupffer cells.Host-resistance models of Listeria monocytogenes or Streptococcuspneumoniae showed an increased resistance following administrationof morphine. This increased host resistance, however, was notdue to an increase in antimicrobial action of sera obtainedfrom mice treated with morphine. The majority of morphine'seffects on the immune system exhibited a flat dose response,suggesting that these effects may be mediated secondarily throughcorticosterone.     

A 13-Week Toxicologic and Pathologic Evaluation of Prolonged Cytochromes P450 Inhibition by 1-Aminobenzotriazole in Male Rats

The pharmacologic, toxicologic, and microscopic effects of 100mg/kg/day of 1-Aminobenzotriazole (ABT), a suicide substrateinhibitor of cytochromes P450, were assessed in male Sprague-Dawleyrats over a 13-week period. Hepatic cytochromes P450 levelsand resorufin dealkylase activity were decreased to less than30% of control values beginning at Day 2 and from Day 8 to Day92. These decreases were not accompanied by overt clinical toxicity,e.g., changes in body weight, food consumption, or clinicalappearance, during the study. Hemoglobin, hematocrit, and erythrocytecounts were slightly decreased at 8, 29, and 92 days and wereaccompanied by increased spleen weights and extramedullary hematopoiesis.Additionally, mean corpuscular hemoglobin concentration, meancorpuscular volume, red cell distribution width, and mean corpuscularhemoglobin were slightly increased at 92 days. Increases inliver weights at 8, 29, and 92 days were accompanied by centrilobularhypertrophy and intracytoplasmic vacuolization consistant withlipid accumulation. Thyroid stimulating hormone (TSH) was slightlyelevated and triiodothyronine and thyroxine were slightly decreasedat 29 days. TSH was also slightly elevated at 8 and 92 days,and thyroid gland weights were increased at 8, 29, and 92 dayswith microscopic evidence of hyperplasia and hypertrophy ofthyroid gland follicular cells. Increased adrenal weights andhypertrophy of the zona fascicularis of the adrenal gland wereobserved at 8, 29, and 92 days. Kidney weights were also increasedat these assessments. Changes in the thyroid gland, the thyroidhormone profile, and the liver may reflect increased synthesisof microsomal enzymes, an effect that is sometimes difficultto demonstrate directly with suicide substrate inhibitors ofcytochromes P450. In general, the effects of daily ABT administrationto male rats at a dose that significantly reduces oxidativemetabolism over a 13-week period were considered to be well-toleratedunder controlled laboratory conditions.     

Vital exhaustion, extent of atherosclerosis, and the clinical course after successful percutaneous transluminal coronary angioplasty

It has been observed that vital exhaustion, a state characterizedby unusual tiredness, increased irritability and feelings ofdemoralization not uncommonly precedes myocardial infarctionin apparently healthy individuals. This observation raised thequestion as to whether vital exhaustion is a marker of subclinicalcoronary disease. To answer that question the condition wasassessed in 105 male patients (mean age 54·8 year) beforeand 2 weeks after successful percutaneous transluminal coronaryangioplasty (PTCA) by the Maastricht questionnaire. Vital exhaustionwas found to be significantly correlated with the number ofdiseased vessels before PTCA and to decrease significantly afterPTCA. However, the association was rather modest (R²=0·08)and most patients remained exhausted after PTCA. During a follow-upperiod of 1·5 years, 32 patients (30%) experienced anew cardiac event (cardiac death, myocardial infarction, coronaryartery bypass grafting, repeat PTCA, a new coronary lesion orrecurrent angina with documented ischaemia). Univariate andmultivariate analyses showed that the number of diseased vessels,hypercholesterolaemia, and vital exhaustion were independentlyassociated with future events. The odds ratios were 3·74(P=0·02), 3·08 (P=0·08) and 3·07(P=0·04), respectively. It is concluded that the tirednesspreceding a cardiac event is only modestly associated with theextent of coronary artery disease and that a state of exhaustionafter PTCA increases the risk for a new cardiac event.     

Circulating Megakaryocytes and Platelet Release in the Lung

1. Megakaryocytes were demonstrated in central venous blood of each of23 patients who underwent cardiac catheterization. Cell counts ranged from0.7 to 5.9 megakaryocytes per ml. of blood; the equivalent of one-third ofthese cells were considered to contain a full complement of cytoplasm. It hasbecome evident that megakaryocytes are normal constituents of blood.

2. In an attempt to quantify megakaryocyte migration from the bone marrow it was calculated that from 20-50 per cent of the mature megakaryocytepopulation enters the blood and ultimately reaches the lungs. The possibilitythat all megakaryocytes migrate from the marrow is not precluded with certainty by these studies.

3. It was estimated that from 7-17 per cent of the body’s platelets are released in the pulmonary capillaries. If all megakaryocytes migrate from thebone marrow, then as much as 33 per cent of the platelet population is delivered to the blood in the lungs.

Submitted on January 15, 1965 Accepted on March 13, 1965