Period Of Drug Administration Research Articles

Grau de desmineralização em osso trabecular e cortical por meio de tomografia computadorizada quantitativa em cães submetidos à terapia com prednisona

Os glicocorticóides são fármacos amplamente utilizados na medicina veterinária, entretanto, além dos efeitos benéficos, o seu emprego pode desencadear uma série de efeitos indesejados. Foi realizado um ensaio clínico em oito cães hígidos com o intuito de avaliar possíveis alterações na densidade mineral óssea após a terapia com prednisona, utilizando a tomografia computadorizada helicoidal. Todos os animais receberam a prednisona via oral na dose diária de 2mg kg-1 de peso durante 30 dias. A densidade mineral óssea foi determinada a partir da obtenção de valores de radiodensidade da região de osso cortical e osso trabecular do corpo vertebral da segunda vértebra lombar, imediatamente antes e após o período de administração do medicamento. O protocolo experimental permitiu a caracterização de significativa (P<0,05) diminuição da radiodensidade do corpo vertebral da segunda vértebra lombar, entretanto não se constatou desmineralização significativa na região cortical. Nenhum dos animais apresentou fratura patológica ao término da administração do medicamento. O presente estudo comprovou que as alterações no metabolismo ósseo de cães submetidos à terapia com prednisona na dose de 2mg kg-1 ocorrem precocemente somente em osso trabecular, tornando-se recomendado um monitoramento dos pacientes para prevenção de fraturas patológicas.

Propofol-Induced Sleep: Efficacy and Safety in Patients with Refractory Chronic Primary Insomnia

Insomnia, defined as difficulty in falling asleep and/or staying asleep, short sleep duration, or poor quality sleep, is a common sleep disorder affecting 30-40% of adult population. We have conducted a randomized, double-blind, placebo-controlled study to test if anesthesia is therapeutically beneficial in patients with refractory chronic primary insomnia. We have assessed the efficacy and safety of propofol-induced sleep in these patients. This study comprised of 103 patients with refractory chronic primary insomnia (including 59 non-pregnant, non-lactating women; 28-60 years) and the participants were randomized to receive either physiological saline (placebo) (n = 39) or 3.0 g/l propofol (n = 64) in a 2-h continuous intravenous infusion for five consecutive nights. The Leeds Sleep Evaluation Questionnaire was used for the subjective assessment of sleep, and polysomnography was used for the objective measurement of sleep architecture and patterns. The assessments were done prior to and at the end of the 5-day treatment and 6 months after treatment period. The adverse effects of the treatment were also recorded. A 2-h continuous intravenous infusion of 3.0 g/l propofol for five consecutive nights improved the subjective and objective assessments of sleep in 64 patients with refractory chronic primary insomnia. This improvement occurred immediately after the therapy and persisted for 6 months. No serious adverse events were noticed during the period of drug administration or 6 months after the treatment. Propofol therapy is an efficacious and safe choice for restoring normal sleep in patients with refractory chronic primary insomnia.

Developmental anomalies of the medial septal area: possible implication for limbic epileptogenesis

The maldevelopment of the midline structures is connected with neurologic disorders. The cavum septum pellucidum (CSP) exists in the fetal period, then it is re-absorbed. The presence of unfused leaflets/fornices may be considered important in the genesis of neurodevelopmental abnormalities inclunding epilepsy. The limbic system includes a group of interconnected gray and white matter structures; in this circuit, the fornix is an important white matter connection with the septum pellucidum. Five children, 3-10 years of age, with epilepsy and an unfused septum pellucidum and fornices on MRI, were evaluated by diffusion tensor imaging-fiber tracking (DTI-FT) in order to explore the integrity of the axonal microenviroment of these structures. The patients had generalized tonic-clonic seizures (GTCS). The electroencephalogram (EEG) showed focal-temporal abnormalities with secondary generalization. Magnetic resonance imaging (MRI) and DTI-FT demonstrated the CSP, and the presence of the fornix's body split into two bundles with the fornices separated. The fornix appears more involved than CSP alone, as suggested by fornix atrophy observed in MTLE. Even if epilepsy is suggested to be a grey matter disorder, changes in the underlying brain connectivity have an important contribution in seizure generation and diffusion. In addition, the interconnections of medial septal area with hyppocampus, amygdala and entorhinal cortex, have led to the hypothesis of functional limbic epilepsy. In our patients, the role of DTI was not conclusive since the definition of the number of unmyelinated fibers responsible for epilepsy could not be demonstrated probably for a limited number of seizures and for a short period of drug administration.

Anti-hypersensitivity effects of Shu-jing-huo-xue-tang, a Chinese herbal medicine, in CCI-neuropathic rats

Aim of the study Shu-jing-huo-xue-tang (SJHXT) (Japanese name: Sokei-kakketu-to), a traditional Chinese herbal medicine composed of 17 crude drugs, has been prescribed over hundreds of years for treatment of chronic pain syndromes. We evaluated if oral SJHXT could suppress neuropathic pain behaviors in rats with chronic constriction injury (CCI) of the sciatic nerve. Materials and methods (1) Rats received repeated oral SJHXT 0.5 or 1.0 g/kg once daily for 14 days starting 24 h after CCI surgery, while neuropathic manifestations were evaluated until day 20 post-CCI. (2) Other groups of rats received single oral SJHXT 1.0 g/kg on day 14 post-CCI. (3) Additional groups of rats received oral SJHXT 1.0 g/kg on day 14 post-CCI, concomitantly with intraperitoneal yohimbine 1 mg/kg or methysergide 5 mg/kg. Neuropathic manifestations, including mechanical allodynia and thermal hyperalgesia, were evaluated with paw withdrawal responses to increasing mechanical pressure and radiant heat, respectively. Results Mechanical allodynia and thermal hyperalgesia developed by day 14 post-CCI. Repeated oral SJHXT for 14 days produced anti-allodynic and anti-hyperalgesic effects that outlasted the period of drug administration. Single oral SJHXT on day 14 also produced significant anti-allodynic and anti-hyperalgesic effects, which were inhibited by yohimbine, an alpha-2 adrenoceptor antagonist, but not by methysergide, a serotonin receptor antagonist. Conclusions Oral SJHXT produced anti-hypersensitivity effects by actions on alpha-2 adrenoreceptors in CCI-neuropathic rats, and chronic oral administration of SJHXT could produce the long-lasting anti-hypersensitivity effects.

Changes in Glitazone Use Among Office-Based Physicians in the U.S., 2003–2009

OBJECTIVELittle is known regarding recent changes in glitazone use.RESEARCH DESIGN AND METHODSInterrupted time series analyses of nationally representative office-visit data using IMS Health's National Disease and Therapeutic Index.RESULTSFrom 2003 through 2005, glitazone use increased steadily. From February 2005 to January 2007, rosiglitazone use decreased by 16% (95% CI −20 to −11) annually; pioglitazone use increased at an annual rate of 14% (9–18). During a period of Food and Drug Administration (FDA) advisories, rosiglitazone use declined sharply from 0.42 million monthly treatment visits (February 2007) to 0.13 million monthly visits (May 2008). Pioglitazone use remained stable, accounting for ∼5.8 million physician visits (77% of all glitazone use) where a treatment was used during the final 12 months of observation.CONCLUSIONSThe combined effect of scientific publications, advisories, and media exposure was associated with a substantial decrease in rosiglitazone use. Despite a class-level FDA advisory, pioglitazone use was not similarly affected.

Should every patient with atrial fibrillation have the rhythm converted to sinus rhythm?

Atrial fibrillation is the most common atrial tachyarrhythmia. Consideration for the potential conversion of atrial fibrillation and the subsequent maintenance of sinus rhythm may be related to underlying pathology. Typically, extra cardiac factors such as thyroid hyperactivity help to determine initial therapy. Intrinsic cardiac factors may also influence the clinician's decision regarding potential cardioversion and maintenance of sinus rhythm. Some acute events such as pericarditis and the effects of cardiac trauma may resolve and result in spontaneous restoration of sinus rhythm. Other cardiac events such as acute myocardial infarction with or without atrial ischemia, valvular disease, and others may result in the precipitation of atrial fibrillation. The major reasons to consider cardioversion, either medically or electrically, are ventricular rate control, hemodynamic improvement, sense of well being, and the avoidance of embolism. Certain clinical situations (e.g., Wolff-Parkinson-White syndrome) require urgent restoration of sinus rhythm in light of the potential for extremely rapid ventricular rates. It has been suggested that all antiarrhythmic drug administration should be initiated in the hospital setting, but the brief period of drug administration in an inpatient setting does not protect the patient from potential, late-onset proarrhythmic events. Both antiarrhythmic drug therapy and electric cardioversion are useful for restoration of sinus rhythm in both acute and chronic atrial fibrillation. The most important negative aspect of drug conversion of atrial fibrillation may be the potential development of a proarrhythmic drug effect. Although controversial, conversion (medical or electrical) is probably indicated in every patient with the first episode of persistent atrial fibrillation, even if the patient is asymptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the reference scaled bioequivalence semi-replicate method with other approaches: Focus on human exposure to drugs

To compare the performance of the reference scaled average bioequivalence (scABE R) method proposed by FDA scientists [Haidar et al., 2008. Pharm. Res. 25, 237–241] with other approaches focusing on the human exposure expressed as the product sample size × periods of drug administration. Simulated bioequivalence studies were generated assuming the partial replicate 3-way crossover design and the classic (2 × 2) crossover design. Intrasubject variability (CV W) values ranged from 15% to 60% and sample sizes from 16 to 54. The procedures examined include: the scABE R method, the classic 0.80–1.25 approach, a levelling-off scaled BE limit (BELscW), and some other scaled bioequivalence limits. To assess the performance of the aforementioned approaches, the typical as well as novel three-dimensional modified power curves were constructed. A new index, termed %Mean Relative Difference (MRD%), was introduced in order to quantitatively compare the performance of the bioequivalence limits. The recently proposed scABE R approach showed the lowest producer risk in particular for highly variable drugs. When exposure was taken into account scABE R resulted in a desired behaviour when CV W was low. For high CV W values the overall performance diminished when geometric mean ratio (GMR) substantially deviated from unity. Application of the MRD% index clearly revealed that the effect of lowering the producer risk at GMR = 1 was totally counterbalanced by the rise of consumer risk at high GMR values. The classic 0.80–1.25 limits were favoured at low intrasubject variability and high exposure, whereas the levelling-off limits demonstrated a preferred overall performance when variability was high and exposure was limited.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients.

Effect of Isoproterenol on Cyclosporine-Induced Nephrotoxicity in Rat

Background Oxidative stress is the main mechanism resulting in cyclosporine-induced nephrotoxicity. Because of its ability to stimulate endogenous melatonin production, isoproterenol is one of the most powerful antioxidant drugs. In this study, we sought to determine the effect of isoproterenol on cyclosporine-induced nephrotoxicity in rats. Materials and methods Thirty two young male Wistar rats were divided into four groups: of group A were controls that received placebo; group B, received intraperitoneal isoproterenol (20 mg/kg/d) alone; group C, intravenous cyclosporine (15 mg/kg/d) alone; and group D, both drugs simultaneously at the same doses and durations namely cyclosporine 1 week after administration of isoproterenol. Blood samples to measure serum urea, creatinine, and melatonin levels were drawn four times for each group: before injection, at the mid period of treatment, at the end of treatment, and 1 week after the last injections. Results Isoproterenol increased mean serum melatonin level in groups B and D rats ( P < .05). With regard to deteriorated renal function [DRF = (urea + creatinine)/2], administration of cyclosporine with (group D) or without (group C) isoproterenol was associated with decreased renal function ( P < .05), although it was more perturbed in the latter instance. Measured DRF at the middle and the end of drug administration periods of A and B (revealed significant differences compared with groups C and D; P < .05). Discussion Although cyclosporine-induced nephrotoxicity is not completely eliminated by isoproterenol, the latter showed some protective effects.

Oral THC produces minimal behavioral alterations in preadolescent rats

Although the oral route has traditionally been used for THC administration during the perinatal period in the rat, most studies administering THC during the postnatal period utilize intraperitoneal (ip) administration. In an effort to utilize the same route of administration in both prenatal and postnatal studies, we administered Δ-9-tetrahydrocannabinol (THC) in sesame oil by gavage during postnatal days 22–40 (equivalent to childhood to early adolescence) to male and female rats. We quantified behavior 40 min after administration in the Accuscan activity monitor on days 22, 29 and 40. In addition, we examined active and passive avoidance behaviors in treated adults. Acutely, THC had subtle effects on activity when measured during the period of drug administration and minimal effects on avoidance behaviors examined up to 140 days of age. Since several groups have found that lower doses of THC administered intraperitoneally to periadolescent rats do produce behavioral alterations, we suspect that the inordinately slow absorption of the drug via the oral route may be responsible for the paucity of significant findings in our study. Therefore, oral administration of THC, particularly under conditions of mild food deprivation, may lead to sub-psychoactive concentrations of the drug within the brain.

Efficacy of doxorubicin coupled to lactosaminated albumin on rat hepatocellular carcinomas evaluated by ultrasound imaging

Background/aims Doxorubicin was conjugated with lactosaminated human albumin, a hepatotropic drug carrier, in order to increase its efficacy in the treatment of hepatocellular carcinoma. In rats bearing hepatocellular carcinomas induced by diethylnitrosamine, lactosaminated human albumin coupled doxorubicin enhanced the drug concentrations in the tumours and lowered those in extrahepatic tissues. The aim of the present study was to investigate the effects of lactosaminated human albumin coupled doxorubicin on the growth of established rat hepatocellular carcinomas induced by diethylnitrosamine. Methods Lactosaminated human albumin coupled doxorubicin and the free drug were i.v. administered to rats twice a week for 4 weeks at the single dose of 1 μg/g. Growth of individual tumours was followed through time by ultrasonography. Results In the control animals injected with saline the mean area of the tracked tumours significantly increased during the whole period of treatment. In the group of rats treated with lactosaminated human albumin coupled doxorubicin the mean area of the followed hepatocellular carcinomas remained practically unchanged. The free drug inhibited tumour growth only in the first period of drug administration. Lactosaminated human albumin coupled doxorubicin also hindered the development of new neoplastic nodules, which was unaffected by the free drug. Conclusions The results support lactosaminated human albumin coupled doxorubicin as a promising agent for a systemic chemotherapy of hepatocellular carcinomas to treat noncurable patients.

Doxycycline: A Pilot Study to Reduce Diabetic Proteinuria

Background: Activity of matrix metalloproteinases (MMPs), the enzymes primarily responsible for the deposition of extracellular matrix proteins, contributes to the pathogenesis of diabetic proteinuria. We evaluated the effect of doxycycline, a potent nonselective MMPs inhibitor, on reduction of proteinuria in diabetic patients. Material and Methods: In a self-control clinical trial, 35 patients with overt diabetic nephropathy (proteinuria >300 mg/24 h) received oral doxycycline 100 mg/day for 2 months. Twenty-four-hour urine volume, Cr and protein excretion were measured at baseline, after 1 and 2 months of treatment, and after 4 months of its discontinuation. Treatment-related side effects were closely monitored and documented. Results: Mean (±SD) 24-hour urine protein was 888 ± 419 mg at baseline, 884 ± 368 mg after 1 month, and 643 ± 386 mg after the 2 months of doxycycline treatment. There was statistically significant reduction in proteinuria at 2 months of treatment vs. at the baseline (p < 0.001). Mean 24-hour urine protein excretion increased to 1,021 ± 422 mg 4 months after doxycycline was discontinued. The changes in serum sodium, potassium, BUN and Cr concentrations, and blood pressure measurements during the 2 months of treatment and follow-up period were not statistically significant. Conclusion: Proteinuria in patients with diabetic nephropathy can be reduced with low dose doxycycline therapy over a 2-month period of drug administration. Further studies are necessary to determine the long-term effect, the optimal dose, and the optimal duration of this potentially novel therapy.

The effects of antipsychotic drugs on GABA A receptor binding depend on period of drug treatment and binding site examined

Changes in GABA A receptors are observed in schizophrenia, with benzodiazepine-sensitive GABA A receptor subtypes being affected differently to other subtypes. However, long-term antipsychotic drug use in schizophrenia may underlie these changes. To test this, we examined the effects of administering a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug on the GABA A receptor agonist (orthosteric) and benzodiazepine (allosteric) binding sites in rat prefrontal cortex. As antipsychotic drugs have delayed maximal therapeutic effects we also examined different drug treatment periods. Male SD rats received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for either 7, 14 or 28 days. Sections of rat brain were then labelled with [ 3H]muscimol, which labels the total population of GABA A receptors, or the benzodiazepine site ligand [ 3H]flunitrazepam in separate saturation binding experiments using quantitative receptor autoradiography. [ 3H]Muscimol binding was enhanced in the prefrontal cortex after 7 days but no differences were observed after longer periods of drug administration. In contrast there was a delayed increase in density of benzodiazepine-sensitive GABA A receptors in the PFC, suggesting that antipsychotic drugs have different effects on different GABA A receptor subtypes. These changes in the properties of GABA A receptor binding following antipsychotic drug administration are not consistent with those observed in schizophrenia and suggest a ‘reshuffling’ in GABA A receptor subtypes over time.

Acute and subchronic effects of amitriptyline 25mg on actual driving in chronic neuropathic pain patients

The acute and subchronic effects of low doses nocturnally administered amitriptyline were compared to placebo in a double-blind crossover randomized study on driving ability and driving-related skills involving seven chronic neuropathic pain patients. Performance testing occurred at the first and last day of each 15-day drug administration period, which was preceded by a 6-day washout phase. A standardized method of measuring driving ability, the on-the-road driving test, was performed on all visits. Patients were instructed to drive with a steady lateral position while maintaining a constant speed of 95 km/h. The primary outcome of the driving test is the Standard Deviation of Lateral Position (SDLP, cm), which is an index of weaving of the car. At the first treatment day, driving performance was significantly impaired in patients after nocturnal administration of 25 mg amitriptyline compared to placebo. The increase in SDLP of 3 cm was higher than the increment generally observed with a blood alcohol concentration of 0.5 mg/ml or higher, the legal limit for driving in many countries. Also, reaction times on a memory test were significantly increased, indicating worse performance after acute treatment of amitriptyline compared to placebo. In contrast, after 2 weeks of treatment, no significant differences were found between amitriptyline and placebo, suggesting that tolerance had developed to the impairing effects of amitriptyline.

Alterations in Body Temperature, Corticosterone, and Behavior Following the Administration of 5-Methoxy-Diisopropyltryptamine (‘Foxy’) to Adult Rats: a New Drug of Abuse

Many drugs are used or abused in social contexts without understanding the ramifications of their use. In this study, we examined the effects of a newly popular drug, 5-methoxy-diisopropyltryptamine (5-MEO-DIPT; 'foxy' or 'foxy-methoxy'). Two experiments were performed. In the first, 5-MEO-DIPT (0, 10, or 20 mg/kg) was administered to rats four times on a single day and animals were examined 3 days later. The animals that received 5-MEO-DIPT demonstrated hypothermia during the period of drug administration and delayed mild hyperthermic rebound for at least 48 h. Corticosterone levels in plasma were elevated in a dose-dependent manner compared to saline-treated animals with minor changes in 5-HT turnover and no changes in monoamine levels. In experiment 2, rats were examined in behavioral tasks following either 0 or 20 mg/kg of 5-MEO-DIPT. The animals treated with 5-MEO-DIPT showed hypoactivity and an attenuated response to (+)-methamphetamine-induced stimulation (1 mg/kg). In a test of path integration (Cincinnati water maze), 5-MEO-DIPT-treated animals displayed deficits in performance compared to the saline-treated animals. No differences were noted in the ability of the animals to perform in the Morris water maze or on tests of novel object or place recognition. The data demonstrate that 5-MEO-DIPT alters the ability of an animal to perform certain cognitive tasks, while leaving others intact and disrupts the endocrine system. 5-MEO-DIPT may have the potential to induce untoward effects in humans.

Oral Rabeprazole 20 Mg Provides More Effective Acid Control Than IV Pantoprazole 40 Mg

Purpose: Intravenous (IV) proton-pump inhibitor therapy is used increasingly in hospitalized patients, even if, in many cases, they can take oral medication. Oral and IV pantoprazole produce equivalent acid suppression; oral rabeprazole produces greater acid suppression than oral pantoprazole. This study compares the antisecretory effects (time pH>3, 4, 5 & 6) produced by standard doses of oral rabeprazole and IV pantoprazole in healthy volunteers. Methods: Double-blind, randomized, two-way crossover study in 38 Helicobacter pylori-negative healthy volunteers. Subjects received oral rabeprazole 20 mg or IV pantoprazole 40 mg once daily for 3 days, with a 14-day (±3) washout period before the second 3-day drug administration period with the crossover drug regimen. Intragastric pH was recorded continuously for a 24-h period after dosing on days 1 and 3 of each treatment phase. Results: Over a 24-hour period, oral rabeprazole produced greater acid suppression than IV pantoprazole on day 1 [pH>3.0 (51.0%, 35.7%; p < 0.001), pH>4.0 (37.7%, 23.9%; p < 0.001), pH>5.0 (24.9%, 14.2%; p < 0.001), pH>6.0 (11.2%, 5.8%; p= 0.024)] and on day 3 [pH>3.0 (68.4%, 51.5%; p < 0.0001), pH>4.0 (54.4%, 37.7%; p < 0.001), pH>5.0 (38.1%, 24.8%; p <0.001), pH>6.0 (17.3%, 11.5%; p= 0.017)]. Over a 10-hour night-time period, oral rabeprazole produced greater acid suppression than IV pantoprazole on day 1 [pH>3.0 (42.8%, 27.8%; p < 0.010), pH>4.0 (30.2%, 18.2%; p= 0.017)] and on day 3 [pH>3 (56.2%, 37.0%; p < 0.001), pH>4 (43.4%, 26.2%; p= <0.002), pH>5 (29.8%, 18.8%; p= 0.024). Conclusions: In healthy subjects, oral rabeprazole provides greater intragastric acid suppression over 24 hours and during the 10-hour nocturnal period on day 1 and 3 than IV pantoprazole. Oral rabeprazole may be an appropriate substitute for IV pantoprazole in patients who can take oral medication. [figure 1]Figure 1

Ongoing In Vivo Studies with Cytoskeletal Drugs in Tau Transgenic Mice

Most drug discovery efforts for Alzheimer's disease (AD) have focused on prevention or clearance of beta-amyloid (Abeta) fibrils or oligomers, with far less attention to prevention of tau abnormalities that lead to neurofibrillary tangles (NFTs). Much evidence now indicates that Abeta multimers can trigger neurodegenerative changes that involve formation of dystrophic neurites and cytoskeletal collapse, possibly due loss of microtubule (MT) stabilization by the tau protein. We have found that several MT-stabilizing agents such as Taxol significantly enhanced neuronal survival in the presence of Abeta and identified agents that enter the brain, a necessity for in vivo testing in animal models of tau pathology. Studies were designed to test two agents in the tau mutant (JNPL3) mouse that develops severe motor deficits at about seven months of age, accompanied by neuropathological markers of tau pathology. In addition to using motor performance tests through the planned period of drug administration, we designed a simple appetitive memory test that required a reduction in ad lib food intake. Although the neurochemical data are still being analyzed, we were surprised to find that all of the JNPL3 mice, whether receiving the drug or not, developed no signs of motor impairment up to 10 months of age. This is considerably beyond the age at which free-fed mice survived and suggests that the food restriction alone may have delayed the pathological process. A study is ongoing with free-fed mice to determine if the drug interventions do have any beneficial effects in these mutant mice.

Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress‐induced decrease in cell proliferation and BDNF expression in rat hippocampus

Clinical studies show better response rates of patients with depression and schizophrenia to combinations of atypical antipsychotics and antidepressants, compared to responses to either type of drugs alone. Animal studies demonstrate that some antipsychotics and antidepressants increase neurogenesis and BDNF expression in the hippocampus, which is reduced in volume in patients with depression or schizophrenia. We hypothesized that the better therapeutic effects of combined treatment seen in schizophrenia and depression patients are related to the additive or synergistic effects of combined treatment on hippocampal neurogenesis and BDNF expression. To test this hypothesis, we investigated the effects of chronic administration of quetiapine, venlafaxine, and their combination, on hippocampal cell proliferation and BDNF expression in rats, when subjected to chronic restraint stress (CRS) during the last 2 weeks of a 3-week drug administration period. We found (1) CRS decreased hippocampal cell proliferation and BDNF expression; (2) chronic administration of quetiapine or venlafaxine dose-dependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS (6 h/day for 14 days); (3) the combination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted effects comparable to those produced by their combination. These results support our hypothesis and can lead to future studies to develop new therapeutic approaches for treatment-resistant depression and the negative symptoms of schizophrenia.

In vivo enhancement of herpes simplex virus thymidine kinase/ganciclovir cancer gene therapy with polyamine biosynthesis inhibition

We have earlier demonstrated that inhibition of polyamine biosynthesis with difluoromethylornithine (DFMO) can be used to enhance the cytotoxicity of herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy in different tumor cell lines. Here, the utility of this treatment combination was tested in vivo in a nude mouse tumor model. First, the effect of DFMO was verified by treating mice bearing subcutaneous 9L rat glioma tumors with 2% DFMO in drinking water. The drug treatment induced almost complete suppression of ornithine decarboxylase activity, and as a result, a strong decrease in intratumoral putrescine and spermidine concentrations, which were normalized 4 days after drug removal. Consequently, the tumors displayed a significant reduction in the proliferation activity that was increased to 20% higher than the normal level at day 4 and returned to normal level 7 days after DFMO removal. Next, 9L tumors with 30% of TK-GFP fusion gene positive cells were induced and the animals were given DFMO and GCV in 2 treatment schemes, with the drug administration periods overlapping either 5 or 2 days. The analysis of tumor size at the end of the treatment revealed that DFMO can enhance HSV-TK/GCV cytotoxicity when the overlap between DFMO and GCV was 5 days, but the result was not significant. However, the 2-day overlap scheme yielded a significantly (p < 0.05, ANOVA) enhanced antitumor effect. In conclusion, the data here confirms that a novel combination of 2 clinically relevant treatment modalities, polyamine deprivation and HSV-TK/GCV suicide gene therapy, can be used synergistically in vivo.

Pharmacokinetics of Fluoxetine in Elderly Men and Women

Fluoxetine is widely prescribed as an antidepressant for geriatric patients. Despite a large scientific literature describing its efficacy and safety, there are few published data describing the pharmacokinetics of fluoxetine in the elderly. Given the common practice of polypharmacy in this population, additional pharmacokinetic information in elderly men and women is needed so that physicians can better assess potential drug-drug interactions. Twenty-five subjects, men and women between ages 65 and 83, received 20 mg of fluoxetine for 1 week followed by 40 mg for 5 weeks. Serum fluoxetine levels were measured during the period of drug administration and for 8 weeks after. The plasma concentration of fluoxetine and norfluoxetine in our subjects was higher than previously reported in the literature. Elderly women had a significantly higher serum level of norfluoxetine than men. The terminal half-life of norfluoxetine was longer in patients over age 75; elderly women had a significantly slower rate of norfluoxetine elimination than similarly aged men.