Drug Distribution in Obesity and following Bariatric Surgery: A Literature Review

Background: The pharmacokinetic variables of drug clearance and volume of distribution are usually corrected for body weight or surface area. Only recently have the relationships which exist between body size, physiologic function and pharmacokinetic variables been evaluated in the obese population. These effects are not widely known, and data on this and the effects of bariatric surgical procedures are scantily documented in the surgical literature. Methods: Literature review. Results: Drugs with a low or moderate affinity for adipose tissue have a moderate increase in the volume of distribution (Vd), and this correlates with the increase in lean body mass (LBM). Highly lipophilic drugs, with some exceptions, show the expected increase in Vd and prolongation of elimination half-life, indicating a marked distribution into adipose tissue. Drug absorption, in general, is slowed by delayed gastric emptying and is normal when gastric emptying is normal or increased. Most drug absorption occurs in the small intestine where duration of drug/mucosal contact is the most important factor. Conclusions: Drugs whose distribution is restricted to LBM should utilize a loading dose based on ideal body weight (IBW). For those drugs which distribute freely into adipose tissue, the loading dose should be based on total body weight (TBW). Adjustment of the maintenance dose depends on clearance rates. In a few cases dosage adjustment depends on pharmacodynamic data, since drug clearance does not conform to these recommendations, for reasons which remain to be defined. Following bariatric surgery, in the absence of delayed gastric emptying or uncontrolled diarrhea, drug absorption rates are usually comparable to the non-operated patient.     

Enhancement of 3H-diazepam binding by SQ 65,396: a novel anti-anxiety agent.

SQ 65,396, a clinically active anti-anxiety agent, enhanced the binding of 3H-diazepam at 1.5 nM. This effect was due to an increase in the affinity for the ligand, without a change in the number of 3H-diazepam binding sites. This action of SQ 65,396 may mediate its anti-anxiety effects by affecting the action of an endogenous modulator of the "benzodiazepine receptor." Several other substances and treatments increase the affinity of 3H-diazepam for its receptors by mechanisms which may be related to the effect produced by SQ 65,396.     

A prospective randomised trial on the effect of monitoring plasma anticonvulsant levels in epilepsy

Summary To evaluate whether knowledge of plasma levels of anti-epileptic drugs has an effect on therapeutic outcome, 127 epileptic outpatients were randomly assigned to two groups (A and B). Plasma levels of group A were reported to the treating physician who attempted to keep the plasma levels within the therapeutic range. The treating physician was not informed of the results of plasma lavel determinations of group B. Data from 105 patients were available for assessment at the end of the study year. Therapeutic results of groups A and B were not significantly different. The reduction in seizure frequency was associated with an increase in plasma concentrations of the anti-epileptic drugs. Thus, under the conditions of the study, knowledge of plasma levels of anti-epileptic drugs did not further improve therapeutic results.

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Zusammenfassung Um festzustellen, ob die Kenntnis des Plasmaspiegels der Antiepileptika das Therapieergebnis verbessern kann, wurden 127 ambulant behandelte Patienten mit Epilepsie in randomisierter Reihenfolge in zwei Gruppen eingeteilt (A und B). Die Plasmaspiegel der Antiepileptika in Gruppe A wurden dem behandelnden Arzt mitgeteilt, der versuchen sollte, die Plasmaspiegel in den Therapeutischen Bereich zu bringen. Die Ergebnisse der Plasmaspiegelbestimmung in Gruppe B (Kontrollgruppe) wurden dem behandelnden Arzt nicht mitgeteilt. Am Ende des Untersuchungsjahres konnten die Daten von 105 Patienten ausgewertet werden. Das Behandlungsergebnis von Gruppe A und von Gruppe B war am Ende des Beobachtungsjahres nicht signifikant verschieden. Die Abnahme der Anfallshäufigkeit ging mit einem Anstieg der Plasmakonzentration der Antiepileptika einher. Somit konnte unter den Bedingungen dieser Studie das Therapieergebnis durch die Kenntnis der Plasmaspiegel der Antiepileptika nicht weiter verbessert werden.

     

Pharmacology of antimigraine drugs

The drugs used in migraine therapy can be divided into two groups: agents that abort an established migraine attack and agents used prophylactically to reduce the number of migraine attacks. Both groups have drugs that are specific for migrainous headaches and that are non-specific, and are used to treat the accompanying headache (analgesics), vomiting (anti-emetics), anxiety (sedatives and anxiolytics), or depression (antidepressants). The main drugs with specific action on migraine include ergot alkaloids (ergotamine, dihydroergotamine), agonists (sumatriptan) or partial agonists (methysergide) at a specific subtype of 5-HT₁-like receptors, -adrenoceptor antagonists (propranolol, metoprolol), calcium antagonists (flunarizine) and anti-inflammatory agents (indomethacin). The pharmacological basis of therapeutic action of several of these drugs is not well understood. In the case of the ergot alkaloids and 5-HT₁-like receptor agonists, however, it is likely that the antimigraine effect is related to the potent and rather selective constriction of the large arteries and arteriovenous anastomoses in the scalp and dural regions. In addition, these drugs inhibit plasma extravasation into the dura in response to trigeminal ganglion stimulation, but it is possible that this effect is related to the selective vasoconstriction in the extracerebral vascular bed. The selectivity of the pharmacological effects of these antimigraine drugs (constriction of the extracerebral arteries and arteriovenous anastomoses, poor penetration into the central nervous system and the absence of an antinociceptive effect even after intrathecal administration) strongly suggests that excessive dilatation in the extracerebral cranial vasculature, probably initiated by a neuronal event, is an integral part of the pathophysiology of migraine.     

Chronic treatment with desipramine caused a sustained decrease of 3,4-dihydroxyphenylglycol-sulphate and total 3-methoxy-4-hydroxyphenylglycol in the rat brain

Summary The 2 major metabolites of norepinephrine (NE), 3,4-dihydroxyphenylglycol-sulphate (DOPEG-SO₄) and free plus conjugated 3-methoxy-4-hydroxyphenylglycol (total-MOPEG), both their endogenous concentrations and their accumulation from the NE-precursors ³H-tyrosine or ³H-dopamine, were determined in the whole rat brain to assess the effect of chronic treatment with desipramine (DMI), imipramine and amitriptyline. DOPEG-SO₄ was decreased 2 h and 24 h after the last administration of DMI (10 mg/kg twice daily for 4, 10 or 20 days) or imipramine (10 mg/kg twice daily for 10 days). When measured within 24 h after the last dose of DMI or imipramine, several schedules resulted in reduced accumulation of total-³H-MOPEG and ³H-NE, while ³H-NE and MOPEG were unchanged in the remaining schedules. These results indicate that DMI retains its ability to decrease NE-turnover over a period of 20 days of treatment. Forty-eight hours or 72 h after the last administration of desipramine and imipramine an overshoot was observed in NE-metabolism, consisting of increased levels of total-³H-MOPEG and endogenous total-MOPEG; DOPEG-SO₄ was some-times concomitantly increased. The overshoot was more consistent after 20 or 10 days of treatment than after 4 days of treatment. This finding, together with a tendency to partial tolerance to the metabolite decreasing effects of DMI, indicate that adaptive changes occur in the NE system after treatment for 10–20 days with DMI or imipramine.Abbreviations Used NE norepinephrine - DOPEG 3,4-dihydroxyphenylglycol - DOPEG-SO₄ DOPEG sulphate ester - MOPEG 3-methoxy-4-hydroxyphenylglycol - total-MOPEG free plus conjugated MOPEG - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - NM normetanephrine - DA dopamine - DMI desipramine     

Effects of antipsychotic drugs on cytokine networks

It has been known since the 1950s that phenothiazines have immunomodulatory effects. This review summarizes recent evidence suggesting that antipsychotic drugs, in particular chlorpromazine and the atypical compound clozapine, influence the production of cytokines. Cytokines, organized in networks of related peptides with pleiotropic functions, are pivotal humoral mediators of infection and inflammation, and they play an important role in hematopoiesis and autoimmunity. Therefore, the effects of antipsychotic drugs on cytokine networks are important for the understanding of immune-mediated side effects of these drugs, e.g. agranulocytosis. In addition, modulation of cytokine production by antipsychotic agents suggests that these drugs might be useful for the treatment of diseases which primarily involve the immune system. Moreover, because cytokines are known to have numerous effects on the CNS, they may mediate effects of antipsychotic drugs on brain functions. Finally, the influence of antipsychotic drugs on cytokine networks is an important confounding factor in studies investigating disease-related immunopathology in psychiatric disorders. This review provides a synopsis of the data published on these topics and outlines future research perspectives.     

药敏纸片的质量控制研究

目的：探讨和研究药敏纸片质量控制的方法。方法：以克拉霉素药敏纸片为例，参照美国临床实验室标准化委员会(NCCLS)和联邦法规全书(CFR)的方法，建立一套药敏纸片质量控制的指标，包括鉴别、检查及含量测定。结果：采用专属性较强、灵敏度较高的TLC法进行鉴别，最低检出量为50μg；制订纸片的的直径、重量差异、含量均匀性及干燥失重作为检查项，采用短小芽孢杆菌(Bacillus pumilus)[CMCC(B)63202]作为检定菌，进行含量测定。结论：建立的克拉霉素药敏纸片质量标准能够控制其质量，可作为其他抗生素药敏纸片建立质量标准的参考。     

帕司烟肼介入凝胶体外抗结核活性及安全性研究

目的 观察帕司烟肼凝胶体外抗结核作用和支气管介入的安全性。方法 手工法、仪器法分别测定帕司烟肼及其凝胶的最小抑菌浓度和最小杀菌浓度及家兔经支气管介入的安全性试验。结果 帕司烟肼凝胶对H37Rv标准株、牛型结核分枝杆菌、草分枝杆菌MIC值分别为0．1、0，1、0．4mg／L，MBC值分别为0，2、0．2和1．6mg／L；帕司烟肼凝胶与帕司烟肼单体MIC、MBC值无显著差异；动物实验表明该药应用安全。结论 帕司烟肼凝胶具有与帕司烟肼单体相同的抗结核菌药效，卡波姆基质不影响帕司烟肼的抗菌活性；以卡波姆为基质的帕司烟肼凝胶应用安全。