The effects of Selective Serotonin Reuptake Inhibitors on newborn adaptation and withdrawal symptoms: A scoping review

BackgroundSince becoming the most frequently prescribed antidepressants in pregnancy, the effects of Selective Serotonin Reuptake Inhibitors on newborns is hotly debated. The aims of this review were to examine terminology and adaptation, withdrawal, and toxicity risks for newborns.MethodScoping review methodology guided the search of electronic databases EBSCOhost, PubMed Central and Springer Online Journals.ResultsOut of 90 articles screened, 23 were eligible for inclusion in the synthesis. Terminology is used interchangeably with poor delineation. Poor Neonatal Abstinence Syndrome is usually mild and transient with newborns experiencing neuro-behaviour and/or respiratory symptoms, initial lowered Apgar score, inhibited respiratory regulation, and hypoglycaemia. Limited studies examined Serotonin toxicity.ConclusionsNewborns exposed to Selective Serotonin Reuptake Inhibitors in-utero are affected, however the evidence is limited due to a lack of high-quality, robust studies to accurately make generalisations regarding Poor Neonatal Adaptation Syndrome or to support the diagnosis over withdrawals. Further research is needed to adequately differentiate between the conditions.     

Selective Serotonin Reuptake Inhibitors and Poststroke Epilepsy: A Population-Based Nationwide Study

Objective

To investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on poststroke epilepsy in a population-based nationwide study.

The FDA Alert on Serotonin Syndrome With Use of Triptans Combined With Selective Serotonin Reuptake Inhibitors or Selective Serotonin‐Norepinephrine Reuptake Inhibitors: American Headache Society Position Paper

(Headache 2010;50:1089‐1099) Background.— In 2006, a US Food and Drug Administration (FDA) alert warned about the potential life‐threatening risk of serotonin syndrome when triptans are used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). This American Headache Society Position Paper further reviews the available evidence of the potential risk of combining triptans with other serotonergic agents. Methods.— Using the Sternbach Criteria or the Hunter Serotonin Toxicity Criteria, the 29 cases used as the basis for the FDA alert were assessed in addition to a more recently published clinical review of 11 case reports of serotonin syndrome resulting from monotherapy, and one report of combination serotonergic agents. Evidence was evaluated according to the American Academy of Neurology Clinical Practice Guideline Process Manual. Results.— Collectively, 40 case reports are available in the literature for subjects receiving either combination or monotherapy of serotonin agonists, all of which are limited to Class IV level of evidence. Of the 29 cases used as the basis for the FDA alert, 10 cases actually met the Sternbach Criteria for diagnosing serotonin syndrome. No cases fulfilled the Hunter Criteria for serotonin toxicity. One case published since the original report does not meet either criteria, and subsequently reported cases involving triptan monotherapy include insufficient details to confirm a diagnosis of serotonin syndrome. Recommendations.— With only Class IV evidence available in the literature and available through the FDA registration of adverse events, inadequate data are available to determine the risk of serotonin syndrome with the addition of a triptan to SSRIs/SNRIs or with triptan monotherapy. The currently available evidence does not support limiting the use of triptans with SSRIs or SNRIs, or the use of triptan monotherapy, due to concerns for serotonin syndrome (Level U). However, given the seriousness of serotonin syndrome, caution is certainly warranted and clinicians should be vigilant to serotonin toxicity symptoms and signs to insure prompt treatment. Health care providers should report potential cases to MedWatch and consider submitting them for publication.     

Calcaneal Bone Mineral Density in Young Adults Prescribed Selective Serotonin Reuptake Inhibitors

Background

Several previous studies have reported both an association between selective serotonin reuptake inhibitors (SSRI) and decreased bone mineral density and increased fractures, but no previous studies have specifically evaluated bone health in young adults who have a history of SSRI use.

Objective

The purpose was to characterize the effect SSRI use in early adulthood on bone mineral density.

Methods

A cross-sectional study was conducted on subjects who voluntarily responded to recruitment methods for the study. Young adults aged 18 to 25 years who were currently or had previously taken an SSRI for a minimum of 3 consecutive months were included in the study. A subject interview was conducted on each patient to collect background information. Each subject’s calcaneal bone mineral density was then measured with an ultrasonometer.

Results

Complete data were collected on 51 subjects. The median duration of SSRI use was 24 ± 54 months. A significant negative correlation was observed between SSRI duration and calcaneal ultrasound T-score (r = –0.53, P < 0.001) which was unchanged in depressed subjects. Subjects on continuous SSRIs for >24 months had a significantly lower median T-score (0.30 ± 0.93) than subjects taking SSRIs for ≤24 months (0.90 ± 0.81; P = 0.0010).

Conclusions

In this young relatively healthy population who were following most of the recommendations to improve bone health, a significant negative correlation was observed between the duration of SSRI use and bone mineral density. Subjects who were on SSRIs for longer than 24 months had a significantly lower T-score. Further large scale longitudinal studies are needed in this younger population to determine the effects of chronic SSRI use on bone health.     

The Use of Selective Serotonin Reuptake Inhibitors in Children and Adolescents with Major Depression

TOPIC: Recent warnings about suicidal thoughts and self-injurious behavior in youth treated with selective serotonin reuptake inhibitors raise fundamental questions about the risk-benefit ratio of this class of medications. METHODS: Data from placebo-controlled trials are used to elucidate the potential risks and benefits of the selective serotonin reuptake inhibitors (SSRIs) in children and adolescent with major depression. This analysis forms the basis of clinical recommendations. SOURCES: The review includes the six large-scale, placebo-controlled trials that have been published over the past decade. These data were augmented by information from regulatory hearings in 2003-2004 and selected open-label reports. CONCLUSIONS: Emerging data from several clinical trials show that the SSRIs have modest effects on childhood depression. In addition, SSRI treatment may be associated with behavioral activation, self-harm, and suicidal ideation. Appropriate use of SSRIs in children and adolescents requires careful diagnostic assessment, evaluation of co-occurring conditions, and diligent monitoring, especially within the first weeks of treatment.     

Review of the Evidence for Treatment of Children with Autism with Selective Serotonin Reuptake Inhibitors

PURPOSE.  To review the potential role of serotonin dysregulation in autism and the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating core deficits and associated symptoms of autism in children. The literature was searched for reports of SSRI use in children with autism. Data are presented from prospective clinical trials that evaluated treatment outcomes.
CONCLUSIONS.  Some SSRIs show moderate success in managing specific behaviors. Only fluoxetine shows evidence of decreasing global autism severity.
PRACTICE IMPLICATION.  Definitive conclusions concerning selection criteria, dosage, safety, and efficacy cannot be drawn given the current state of evidence.     

Selective Serotonin Reuptake Inhibitors Versus Tricyclic Antidepressants in Young Patients: A Meta-analysis of Efficacy and Acceptability

Purpose

A meta-analysis comparing the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) in depressed children, adolescents, and young adults was performed.

Methods

A comprehensive literature search of the PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to December 2013. Only clinical trials that randomly assigned one SSRI or TCA to patients aged 7 to 25 years who met the diagnostic criteria for unipolar depressive disorder were included. Primary efficacy was determined by the pooling of standardized mean differences (SMDs) calculated from the difference in the reduction in mean depression rating scale scores for the 2 antidepressants. Acceptability was determined by pooling the risk ratios (RRs) of dropouts for all reasons and for adverse effects as well as the suicide-risk outcome.

Findings

Five trials with a total of 422 patients were considered to be eligible for inclusion. SSRIs were significantly more effective than TCAs in primary efficacy (SMD = −0.52; 95% CI, −0.81 to −0.24; P = 0.0003). Patients taking SSRIs had a significantly greater response to depressive symptoms than patients taking TCAs (RR = 1.55; 95% CI, 1.04 to 2.29; P = 0.03). On an individual SSRI basis, fluoxetine had a significantly greater efficacy than TCAs (SMD = −0.82; 95% CI, −1.34 to −0.29; P = 0.003). On an individual TCA basis, only imipramine was not significantly worse than SSRIs (SMD = −0.27; 95% CI, −0.56 to 0.02; P = 0.06). Significantly more patients taking TCAs discontinued treatment than patients taking SSRIs (35.8% vs 25.1%; RR = 0.70; 95% CI, 0.52 to 0.93; P = 0.02).

Implications

SSRI therapy has a superior efficacy and is better tolerated compared with TCA therapy in young patients.     

Triptans,Serotonin Agonists,and Serotonin Syndrome (Serotonin Toxicity): A Review

(Headache 2010;50:264‐272) The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5‐HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5‐HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.     

Application of pharmacokinetic-pharmacodynamic modelling in management of QT abnormalities after citalopram overdose

Objective

To develop guidelines for the management of QT prolongation after citalopram overdose, including decontamination with single-dose activated charcoal (SDAC) and cardiac monitoring.

Design

Simulation study using a previously developed pharmacokinetic-pharmacodynamic (PKPD) model which predicted the time-course of QT prolongation and the effect of citalopram dose and use of SDAC on QT prolongation.

Main measures and results

The previously developed PKPD model was used to address the following in patients following citalopram overdose: (1) Above what dose should patients be decontaminated? (2) Above what dose should patients have cardiac monitoring? (3) For what period of time should patients be monitored? The primary outcome was QT,RR combinations above an abnormal threshold as a surrogate predictor of torsades de pointes. Simulations were performed using MATLAB for an overdose patient with typical demographics: 30-year-old female with a heart rate of 79?bpm taking citalopram therapeutically. The simulations showed: (1) There was significant benefit associated with the administration of SDAC to patients following citalopram overdose ingesting >?600?mg; (2) With citalopram overdoses >?1,000?mg it was advisable to give SDAC and cardiac monitor the patient; (3) The risk of developing future abnormal QT,RR combinations was less than 1% in patients with normal QT,RR combinations up to 13?h post-dose, so the minimum monitoring time for citalopram overdoses >?1,000?mg should be 13?h. Recommended dose levels for intervention should be lowered in older patients and patients with tachycardia, while men are less sensitive to QT prolongation.

Conclusions

Guidelines for the management of QT prolongation after citalopram overdose were developed. We believe the model will help clinicians to decide which patients to decontaminate and monitor.     

感应性音乐聆听联合抗抑郁剂治疗对烧伤创面愈合的影响

目的观察感应性音乐聆听 选择性5-羟色胺再摄取抑制剂(SSRIs)治疗对中、重度烧伤患者情绪及创面愈合的影响。方法将烧伤专科的热力烧伤住院患者,于烧伤后3天内按焦虑、抑郁情绪分值评分,选择有焦虑、抑郁情绪者随机分配为试验组(28例)及对照组(27例)。试验组采用感应性音乐聆听 SSRIs,对照组采用常规烧伤治疗,治疗30天。观察两组治疗前后焦虑、抑郁分值及创面愈合情况。结果试验组治疗前后抑郁、焦虑情绪分值差分别为13.7±6.43和6.43±2.72,对照组抑郁、焦虑情绪差值分别为4.74±6.75,4.44±3.36。两组比较其差异有统计学意义(P<0.05)。与对照组比较,试验组创面愈合时间缩短(P<0.05)。烧伤指数与焦虑情绪及抑郁情绪之间呈正相关(P<0.05)。结论焦虑、抑郁情绪与烧伤指数密切相关,感应性音乐聆听 SSRIs治疗能改善焦虑抑郁情绪,同时能缩短烧伤后创面愈合时间。     

The effects of fructose-1,6-diphosphate on haemodynamic parameters and survival in a rodent model of propranolol and verapamil poisoning

Background. Fructose-1,6-diphosphate (FDP) is a metabolite in the glycolytic pathway created from glucose. Exogenously administered FDP increases the yield of ATP from anaerobic glycolysis. FDP reduces ischaemic tissue area in experimentally-induced cerebral and myocardial infarction and improves haemodynamics post-cardiac bypass. We hypothesised that FDP improves haemodynamics in propranolol and verapamil poisoning. Method. Anesthetized Wistar rats were instrumented to record BP, heart rate (HR), cardiac output (CO) and QRS-duration. Propranolol or verapamil were infused continually. When BP dropped by 50%, propranolol-poisoned rats received one of 10% FDP125 mg/kg or 10% FDP250 mg/kg loading dose over 20 minutes followed by infusion 20 mg/kg/h. Verapamil-poisoned rats received the higher dosing regimen of FDP250. Controls received comparable volumes of 10% glucose. Haemodynamic time-points were compared for FDP to control by unpaired t-test or Mann–Whitney test as appropriate (p <?0.05). Survival was assessed using Kaplan–Meier survival analysis. Results. FDP-treated animals survived significantly longer than glucose-treated controls at both doses in propranolol poisoning and in verapamil-poisoning. In propranolol poisoning, FDP250-treated animals showed a statistically significant increase in BP. However, there was no significant difference in cardiac output at this dose. There were also no significant differences in any haemodynamic parameters compared to control at the lower FDP dose in propranolol poisoning or in verapamil poisoning. Conclusion. FDP improved survival for both toxicants with an improvement in haemodynamics at the higher dose in propranolol poisoning. Future research could examine the efficacy of FDP in other beta-blocker and calcium channel-blocker poisoning as well as in concert with established inotropic therapies in drug-induced cardiovascular collapse.     

Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder.

OBJECTIVES: Whether the effect of tricyclic antidepressants on Pain Disorder arises from their noradrenergic or serotonergic actions or both remains unclear. We compared the selective serotonin reuptake inhibitor (SSRI) citalopram and the noradrenergic reuptake inhibitor (NARI) reboxetine in outpatients with Pain Disorder. We also distinguished the drugs' analgesic and antidepressant effects. METHODS: In this 8-week, randomized double-blind study, 35 patients with a DSM-IV-TR diagnosis of Pain Disorder were randomly assigned to receive either citalopram 40 mg/day (N=17 patients) or reboxetine 8 mg/day (N=18). The Present Pain Intensity (PPI) scale and the Total Pain Rating Index (tPRI) of the McGill Pain Questionnaire were used to measure the effect on pain symptoms. Changes in the Zung Self-Rating Depression Scale (Zung-D) scores were evaluated to monitor a possible antidepressant effect. For all patients who had at least one assessment, an intent-to-treat analysis was performed. RESULTS: No significant differences were found in the demographic variables or clinical characteristics of the two treatment groups. In the citalopram group, PPI and tPRI scores measured at baseline decreased after treatment (tPRI: 41.9 vs. 30.0, p=.004; PPI: 3.5 vs. 2.8, p=.045) whereas in the reboxetine group differences were not statistically significant (tPRI: 35.2 vs. 31.5; PPI: 3.7 vs. 3.1). The Zung-D showed no significant changes between baseline and endpoint assessment in either group. CONCLUSIONS: Our study suggests that the SSRI citalopram may have a moderate analgesic effect in patients with Pain Disorder, and that this analgesic activity appears to be not correlated to changes in depressive scores. If confirmed in a larger sample, this evidence suggests that patients who are intolerant or resistant to tricyclic antidepressants, may be treated with SSRIs.     

Safety and Efficacy of Meso-2,3-Dimercaptosuccinic Acid (DMSA) in Children with Elevated Blood Lead Concentrations

Objective: To evaluate the safety and efficacy of meso-2,3-dimercaptosuccinic acid in the treatment of children with lead toxicity. Design: This was an open-label study in 59 children 12–65-months old, with pretreatment whole-blood lead levels of 25–66 μg/dL, who received 116, 26–28 day courses of oral dimercaptosuccinic acid, while residing either in the Pediatric Clinical Research Unit of the Johns Hopkins Hospital or in lead-safe housing during the outpatient portion of the study. Results: All, who completed the study, showed sharp decreases in blood lead concentration during therapy, but 2–3 weeks following completion of drug therapy, blood lead concentration rebounded to an average of 58% (23 μg Pb/dL of whole blood) of their average pretreatment blood lead concentration (40 μg Pb/dL of whole blood). There were no adverse reactions attributable to dimercaptosuccinic acid; however, 2 of the 59 patients were reexposed to defective lead paint and experienced sharp increases in blood lead concentration while on therapy. In one instance, the child's blood lead concentration increased from 20 to 90 μg Pb/dL whole blood in 1 week. Other unexpected events were discussed in the text. Conclusions: Dimercaptosuccinic acid is apparently safe and does mobilize lead into the urine, but not the essential metals, zinc and copper. Reexposure is always a danger; therefore, all children, while on therapy, should be monitored for their blood lead concentration at weekly intervals during and immediately after therapy. No conclusions can be drawn from this study regarding long-term beneficial effects, if any, of this drug on late neurocognitive outcome.     

血液灌流救治重度有机磷农药中毒患者的疗效与护理

目的探讨血液灌流救治重度有机磷农药中毒患者的临床疗效及护理方法。方法将48例重度有机磷农药中毒患者随机分为血液灌流组和常规治疗组。常规治疗组22例接受洗胃、补液、利尿、导泻、解磷定及阿托品等药物治疗；血液灌流组26例在常规治疗的基础上给予血液灌流1—3次，并给予相应观察与护理。结果与常规治疗组比较，血液灌流组的昏迷至清醒时间和住院天数均缩短，阿托品总用量少，治愈率高，差异均有统计学意义（P〈0．05）。结论血液灌流配合常规内科治疗抢救重度有机磷农药中毒患者的效果好，治疗过程中应给予患者相应的护理。     

Eight hours' inhalation of prostacyclin (PGl2) in healthy lambs: Effects on tracheal,bronchial, and alveolar morphology

Objective To study potential toxic effects of long-term (8 h) inhaled prostacyclin (PGI₂) on respiratory tract tissues.Design In a prospective, randomized order, either PGI₂ (n=7) or normal saline (n=7) was aerosolized during a time period of 8 h in healthy lambs.Setting Institute for Surgical Research of the Ludwig-Maximilians University of Munich.Animals 14 healthy, anesthetized, ventilated lambs.Interventions All animals were endotracheally intubated followed by tracheotomy. PGI₂ solution or normal saline was administered with a jet nebulizer (delivery rate 4–10 ml/h; mass median diameter of aerosol particles 3.1 m).Measurements and results Histomorphological changes after 8-h inhalation of PGI₂ solution were compared to those after 8-h inhalation of normal saline. Tracheal and bronchoalveolar tissues were examined by light and electron microscopy in order to assess tissue damage induced by inhaled PGI₂. Pathological changes were ranked by a blinded observer following a graduation system ranging from absence of pathological changes to maximal pathological changes. Abnormalities were restricted to the trachea (focal flattening of the epithelium, loss of cilia, slight inflammatory cell infiltration) and alveolar tissue (focal alveolar septal thickening with slight inflammatory cell infiltration), but no statistically significant differences between the PGI₂ and control groups were encountered.Conclusion Our findings indicate the absence of PGI₂ aerosol-related respiratory tissue damage after 8-h inhalation of PGI₂.PGI₂ (Flolan) was supplied by Wellcome, London, UK. The study was supported, in part, by the Deutsche Forschungsgemeinschaft, grant zw 37/4-1     

Inhalation of prostacyclin (PGI2) for 8 hours does not produce signs of acute pulmonary toxicity in healty lambs

Objective To study the potential side effects and toxicity of inhaling prostacyclin (PGI₂) aerosol for 8 h.Design In a prospective, randomized study 14 healthy lambs received either PGI₂ (n=7) or 0.9% NaCl (n=7) as an aerosol for 8 h.Setting Institute for Surgical Research of the Ludwig-Maximilians-University of Munich.Interventions All animals were studied under general anesthesia in a prone position. They were first intubated endotracheally and later tracheotomized. PGI₂ solution (median dose 28 ng/kg per min) or 0.9% NaCl was administered with a jet nebulizer (delivery rate 4–10 ml/h; mass median diameter of aerosol particles 3.1 m). Bronchoalveolar lavage was performed before and after the inhalation period to collect epithelial lining fluid of alveoli.Measurements and results Hemodynamic and respiratory parameters, systemic resorption (plasma levels of 6-keto-prostaglandin-F1), in vitro bleeding time, collagen-induced platelet aggregation and global biochemical and cellular composition of the epithelial lining fluid were examined in order to assess the sie effects and signs of acute pulmonary toxicity induced by inhaled PGI₂. No statistically significant differences were found between the PGI₂ and the control groups for any of the parameters examined.Conclusion Inhalation of PGI₂ (28 ng/kg per min) over a period of 8 h in healthy lambs does not produce major side effects or acute pulmonary toxicity.PGI₂ (Flolan) was supplied by Wellcome, London, UKThe study was supported, in part, by the Deutsche Forschungsgemeinschaft, grant zw 37/4-1     

Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo

Alkoxyalkyl esters of acyclic nucleoside phosphonates have previously been shown to have increased antiviral activity when they are administered orally in animal models of viral diseases, including lethal infections with vaccinia virus, cowpox virus, ectromelia virus, murine cytomegalovirus, and adenovirus. 9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was previously shown to have activity against hepatitis B virus (HBV) in vitro. To assess the effect of alkoxyalkyl esterification of (S)-HPMPA, we prepared the hexadecyloxypropyl (HDP), 15-methyl-hexadecyloxypropyl (15M-HDP), and octadecyloxyethyl (ODE) esters and compared their activities with the activity of adefovir dipivoxil in vitro and in vivo. Alkoxyalkyl esters of (S)-HPMPA were 6 to 20 times more active than unmodified (S)-HPMPA on the basis of their 50% effective concentrations in 2.2.15 cells. The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro. HDP-(S)-HPMPA retained full activity against HBV mutants resistant to lamivudine (L180M, M204V), but cross-resistance to a mutant resistant to adefovir (N236T) was detected. HDP-(S)-HPMPA is orally bioavailable and provides excellent liver exposure to the drug. Oral treatment of HBV transgenic mice with HDP-(S)-HPMPA, 15M-HDP-(S)-HPMPA, and ODE-(S)-HPMPA for 14 days reduced liver HBV DNA levels by roughly 1.5 log units, a response equivalent to that of adefovir dipivoxil.9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] is an acyclic nucleoside phosphonate which Holý and coworkers first reported in 1986 (7, 8, 26). (S)-HPMPA was the first acyclic nucleoside phosphonate, a growing and important class of antiviral compounds which now includes cidofovir, adefovir [9-(2-phosphonomethoxyethyl)adenine], and tenofovir [9-(2-phosphonomethoxypropyl)adenine], which are used for the treatment of cytomegalovirus (CMV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) infections, respectively (6). In this paper, we report on the synthesis and evaluation of several alkoxyalkyl ester prodrugs of (S)-HPMPA in an attempt to find oral treatments for HBV infection more effective than the currently approved antivirals.(S)-HPMPA is a broad-spectrum antiviral which was shown to inhibit the replication of a wide variety of double-stranded DNA viruses, including orthopoxviruses, herpesviruses, adenoviruses, iridoviruses, and papovaviruses (6). (S)-HPMPA was also reported to be active in vitro against HBV replication in HB611 cells (29) and 2.2.15 cells (11) and to have 50% effective concentrations (EC₅₀s) of 1.15 and 1.5 μM, respectively. Numerous reports have indicated that (S)-HPMPA lacks activity against HIV type 1 (HIV-1) (2, 5, 12). However, alkoxyalkyl esters of (S)-HPMPA, such as hexadecyloxypropyl-(S)-HPMPA [HDP-(S)-HPMPA] and octadecyloxyethyl-(S)-HPMPA [ODE-(S)-HPMPA], exhibit EC₅₀s against HIV-1 in the low nanomolar range, while unmodified (S)-HPMPA is virtually inactive in vitro (13). HDP-(S)-HPMPA exhibits multiple-log increases in antiviral activity in vitro compared with the activity of unmodified (S)-HPMPA against vaccinia virus, cowpox virus, human CMV and murine CMV (3), and adenovirus (10). HDP-(S)-HPMPA is orally bioavailable and is active in vitro against lethal vaccinia virus and cowpox virus infections (24) and against lethal murine CMV infections (25). To assess the effect of alkoxyalkyl esterification of (S)-HPMPA on its in vitro and in vivo anti-HBV activity, we synthesized HDP-(S)-HPMPA, 15-methyl-HDP-(S)-HPMPA [15M-HDP-(S)-HPMPA], and ODE-(S)-HPMPA and evaluated their in vitro activities against HBV replication as well as the cellular uptake and conversion of HDP-(S)-[8-¹⁴C]HPMPA to (S)-HPMPA diphosphate (HPMPApp) in HepG2 cells. Using HDP-(S)-[8-¹⁴C]HPMPA, we also evaluated the oral pharmacokinetics and the level of drug exposure in the plasma, livers, and spleens of mice. Finally, the oral activities of the HDP, ODE, and 15M-HDP esters of (S)-HPMPA were assessed in HBV transgenic mice (15, 17, 21); and their activities were compared with the in vivo activity of adefovir dipivoxil, a compound licensed for use for the treatment of HBV infection.     

除草剂2,4-D丁酯的GC/MS检测及其在中毒患者诊治中的应用

目的建立除草剂2,4-D丁酯的气相色谱-质谱（GC／MS）检测方法,用于临床中毒患者的检测。方法以乙酸乙酯提取血液中2,4D丁酯,采用GC／MS检测。定性采用全扫描法（SCAN）,定量采用选择离子法（SIM）,离子选择m／z175、185、276。结果2,4-D丁酯在10～1500ng／ml成线性,方程为Y=10．565X-1203．5,R=0．9941,标加1000ng／ml浓度的2,4-D丁酯于血液,平均回收率为94．6％,RSD=7．1％;2,4-D丁酯最低检出浓度为3ng／ml（S1M）,信噪比S／N=3;日内精密度RSD为4．1％,日间精密度RSD为5．8％。结论所建方法灵敏、快速、线性范围好,可用于2,4-D丁酯中毒患者的检测。     

地西泮和德巴金联合抗惊厥及连续肾脏替代治疗毒鼠强中毒患者

目的探讨地西泮和德巴金联合抗惊厥及连续肾脏替代治疗(CRRT)对毒鼠强的清除作用。方法采用静脉微量注射泵静脉注射地西泮和德巴金,同时应用CRRT治疗重度毒鼠强中毒。结果本组患者入院后1 h内抽搐得到有效控制,经CRRT 1～4次治疗,7例重度中毒患者均成功获救。结论 CRRT 加地西泮、德巴金微量注射泵静脉注射的方法治疗毒鼠强中毒是目前最有效的治疗手段。