Effect of recent seasonal influenza vaccination on serum antibody responses to candidate pandemic influenza A/H5N1 vaccines: A meta-analysis.

Recent studies have suggested that among those receiving seasonal influenza vaccine (SIV), reduced immunogenicity is observed in recently vaccinated (RV; within the past season or 2) persons when compared with those not recently vaccinated (NRV). We performed a meta-analysis to assess the effect of recent immunization with SIV on serum H5 hemagglutination inhibition (HAI) antibody responses after influenza A/H5N1 vaccination using data from a series of randomized controlled trials. The primary outcome was seroconversion measured by HAI assays following receipt of 2 doses of H5N1 vaccine. The geometric mean titer (GMT) of serum HAI antibody after vaccination was the secondary outcome. Analyses were performed using propensity score (PS) matching. The PS for each individual in the meta-analysis cohort was calculated using logistic regression and covariates included age, gender, race, antigen dose, adjuvant, statin use and vaccine manufacturer. 2015 subjects enrolled in 7 clinical trials were eligible for inclusion in the meta-analysis cohort; among these, 915 (45%) were RV. 901 RV subjects were matched (1:1) with replacement to a subject who was NRV. Subjects who received SIV within the previous season were significantly less likely to seroconvert following H5N1 vaccination (adjusted odds ratio 0.76; 95%CI 0.60-0.96; p = 0.024), and the GMT was 18% higher among NRV subjects (GM ratio of HAI antibody 1.18; 95%CI 1.04-1.33; p = 0.008). Further work is needed to better define the effects of, and mechanisms contributing to, reduced immune responses to H5N1 vaccine among RV subjects.

In utero antiepileptic drug exposure: fetal death and malformations.

BACKGROUND: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach. OBJECTIVE: To determine if fetal outcomes vary as a function of different in utero AED exposures. METHODS: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69). RESULTS: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect. CONCLUSIONS: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children.

OBJECTIVE: Intranasal influenza vaccine has proven clinical efficacy and may be better tolerated by young children and their families than an injectable vaccine. This study determined the potential cost-effectiveness (CE) of an intranasal influenza vaccine among healthy children. METHODS: We conducted a CE analysis of data collected between 1996 and 1998 during a prospective 2-year efficacy trial of intranasal influenza vaccine, supplemented with data from the literature. The CE analysis included both direct and indirect costs. We enrolled 1602 healthy children aged 15 to 71 months in year 1, 1358 of whom were enrolled in year 2. One or 2 doses of intranasal influenza vaccine or placebo were administered to measure the cost per febrile influenza-like illness (ILI) day avoided. RESULTS: During the 2-year study period, vaccinated children had an average of 1.2 fewer ILI fever days/child than unvaccinated children. In an individual-based vaccine delivery scenario with vaccine given twice in the first year and once each year thereafter at an assumed base case total cost of $20 for the vaccine and its administration (ie, per dose), CE was approximately $30/febrile ILI day avoided. CE ranged from $10 to $69/febrile ILI day avoided at $10 to $40/dose, respectively. In a group-based delivery scenario, vaccination was cost saving compared with placebo and remained so if vaccine cost was <$28 (the break-even price per dose). In the individual-based scenario, vaccination was cost saving if vaccine cost was <$5. In this scenario, nearly half of lost productivity in the vaccine group was attributable to vaccine visits, which overshadowed the relatively modest savings in ILI-associated costs averted. CONCLUSIONS: Routine use of intranasal influenza vaccine among healthy children may be cost-effective and may be maximized by using group-based vaccination approaches. cost-effectiveness, influenza, vaccine, children.

Measles virus-specific immunoglobulin G isotype immune response in early and late infections.

A total of 154 human serum samples (32 acute-phase and 22 convalescent-phase serum samples obtained within a week and between days 8 and 26 after the onset of rash, respectively, and 100 samples drawn from healthy immune adults) were processed by an immunofluorescence assay for the detection of immunoglobulin M (IgM), total immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 measles virus-specific antibodies. In the acute phase, IgG1 was seen first, followed by IgG2, IgG3, and IgG4 responses, the mean seropositivity of which gradually increased during convalescence, reaching 100% (standard deviation [SD], 84 to 100%), 57% (SD, 34 to 80%), 86% (SD, 66 to 100%), and 86% (SD, 66 to 100%), respectively. IgG2 rose and fell in connection with IgG3 subclass antibodies, showing a rate of detection of IgG2 and/or IgG3 subclass antibodies of 95.5% (range, 100 to 86.5%) in the convalescent phase of infection. The mean percentage of measles IgG2 and IgG3 seropositivity dropped significantly during the memory phase, to 2% (range, 2 to 6%) and 3% (range, 3 to 7%), respectively (P < 0.05); meanwhile IgG1 and IgG4 subclass responses remained relatively unmodified in samples obtained years after infection (mean 100% [SD, 96 to 100%] and 86% [SD, 79 to 93%], respectively). Results obtained defined two highly different immune isotypic response patterns. One pattern is restrictive to IgG2 and/or IgG3 in the convalescent phase and is kinetically similar to the IgM antibody response, so its detection could be referred to as a recent viral activity. On the other hand, IgG1 and IgG4 were detected in both the convalescent and memory phases of the immune response, but their isolated occurrence without IgG2 and IgG3 could be related to the long-lasting immunity.

[Resurgence of measles in the province of Cordoba, Argentina, in 2000]. / Resurgimiento de sarampión en ia provincia de Córdoba, Argentina, en 2000.

Since 1993, ministers of health of countries of America established as a goal the eradication of measles by the year 2000. As a consequence of measles eradication vaccination strategy there has been a reduction in the incidence of reported cases. Despite that, measles has continued occurring in epidemic outbreaks in many Argentinian provinces. This paper describes and analyzes the outbreak which occurred at Córdoba province, in 2000. Out of 46 serum samples analyzed from suspected cases, 6 (13.3%) were confirmed as measles by indirect immunofluorescence and enzyme immunoassays. All of them were detected in Cordoba city among both without vaccination data and unvaccinated individuals. The epidemiological links among the measles cases could be established although the geographic source of measles importation as well as the primary infection source remain unknown. The highest measles incidence was observed in the group > or = 20 year old (50%), followed by the pre-school age group (< or = 4 year old, 33.3%). The active vaccination data directed against the suspected case contacts along with a high measles population immunity probably contributed to restrict the 2000 outbreak.

Resurgimiento de sarampión en ia provincia de Córdoba, Argentina, en 2000. / [Resurgence of measles in the province of Cordoba, Argentina, in 2000]

Since 1993, ministers of health of countries of America established as a goal the eradication of measles by the year 2000. As a consequence of measles eradication vaccination strategy there has been a reduction in the incidence of reported cases. Despite that, measles has continued occurring in epidemic outbreaks in many Argentinian provinces. This paper describes and analyzes the outbreak which occurred at Córdoba province, in 2000. Out of 46 serum samples analyzed from suspected cases, 6 (13.3

) were confirmed as measles by indirect immunofluorescence and enzyme immunoassays. All of them were detected in Cordoba city among both without vaccination data and unvaccinated individuals. The epidemiological links among the measles cases could be established although the geographic source of measles importation as well as the primary infection source remain unknown. The highest measles incidence was observed in the group > or = 20 year old (50

), followed by the pre-school age group (< or = 4 year old, 33.3

). The active vaccination data directed against the suspected case contacts along with a high measles population immunity probably contributed to restrict the 2000 outbreak.

Resurgimiento de sarampión en ia provincia de Córdoba, Argentina, en 2000 / [Resurgence of measles in the province of Cordoba, Argentina, in 2000]

Since 1993, ministers of health of countries of America established as a goal the eradication of measles by the year 2000. As a consequence of measles eradication vaccination strategy there has been a reduction in the incidence of reported cases. Despite that, measles has continued occurring in epidemic outbreaks in many Argentinian provinces. This paper describes and analyzes the outbreak which occurred at Córdoba province, in 2000. Out of 46 serum samples analyzed from suspected cases, 6 (13.3

) were confirmed as measles by indirect immunofluorescence and enzyme immunoassays. All of them were detected in Cordoba city among both without vaccination data and unvaccinated individuals. The epidemiological links among the measles cases could be established although the geographic source of measles importation as well as the primary infection source remain unknown. The highest measles incidence was observed in the group > or = 20 year old (50

), followed by the pre-school age group (< or = 4 year old, 33.3

). The active vaccination data directed against the suspected case contacts along with a high measles population immunity probably contributed to restrict the 2000 outbreak.

A comparison of the behavioural effects of 5-HT2A and 5-HT2C receptor agonists in the pigeon.

Activity at the 5-HT2A receptor versus that of the 5-HT2C receptor was studied in three behavioural paradigms. In pigeons trained to discriminate 0.32 mg/kg of 1-(2,5-diemethoxy-4-iodophenyl)-2-aminopropane (DOI) (a mixed 5-HT2A/C receptor agonist) from vehicle, quipazine (0.1-1 mg/kg) and m-chlorophenylpiperazine (mCPP) (1-3 mg/kg) substituted for DOI in a dose-related manner, and this generalization was blocked by MDL100907 (0.0001-0.01 mg/kg), a selective 5-HT2A receptor antagonist. RO60-0175 (a relatively selective 5-HT2C agonist) induced partial substitution at 3 mg/kg that was antagonized by both MDL100907 and by 3 mg/kg of SB242084, a relatively selective 5-HT2C antagonist. MK212 (a mixed 5-HT2C/A agonist) induced partial substitution that was antagonized by SB242084, but not by MDL100907. On a progressive ratio 5 operant schedule (PR5) for food reinforcement, DOI, quipazine, mCPP, MK212 and R060-0175 decreased the break point; mCPP, DOI, MK212 and quipazine also induced vomiting. Although MDL100907 antagonized both the reductions of break point and vomiting, SB242084 only partially attenuated the decrease in break point observed with MK212 and DOI, and was unable to eliminate vomiting. Thus pharmacological activity at the 5-HT2A receptor can be behaviourally distinguished from pharmacological activity at the 5-HT2C receptor in the pigeon. Furthermore, the decrease in the break point of a PR5 schedule induced by 5-HT2C receptor agonists may be related to decreased appetite, whereas that induced by 5-HT2A receptor agonists may be due to unrelated factors, such as emesis.

The novel 5-Hydroxytryptamine(1A) antagonist LY426965: effects on nicotine withdrawal and interactions with fluoxetine.

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.

Diminution of the anti-polyribosylribitol phosphate response to a combined diphtheria-tetanus-acellular pertussis/Haemophilus influenzae type b vaccine by concurrent inactivated poliovirus vaccination.

BACKGROUND: Prelicensure studies of Haemophilus influenzae type b vaccines (Hib) and diphtheria-tetanus-acellular pertussis vaccines (DTaP) were evaluated with concurrent oral poliovirus vaccine (OPV). However, inactivated poliovirus vaccine (IPV) is now recommended. A trial was conducted in which infants received a DTaP and Hib vaccine, separately (+) or combined (/), with either all OPV, all IPV or sequential IPV-OPV for the primary series of vaccinations. METHODS: In this protocol 567 infants were equally randomized to receive one of the following: Reference Arm A, DTaP + Hib + OPV; Treatment Arm B, DTaP/Hib + OPV; Treatment Arm C, DTaP/Hib + IPV at 2 and 4 months and OPV at 6 months; or Treatment Arm D, DTaP/Hib + IPV. antibodies against all administered antigens were measured at 7 months of age. Children with an antibody response to Hib (anti-polyribosylribitol phosphate (anti-PRP) <0.15 microg/ml had an antibody titer repeated after the toddler booster immunization. RESULTS: A significant diminution in the anti-PRP response was observed at 7 months of age in children given two or three doses of IPV concurrently with DTaP/Hib, compared with the groups given OPV. The geometric mean concentration of anti-PRP, percentage of children with > or = 0.15 microg/ml and percentage of children with > or = 1.0 microg/ ml, respectively, were: A, 4.4, 98%, 81%; B, 3.2, 94%, 78%; C, 1.3, 86%, 58% and D, 1.2, 84%, 53%. CONCLUSION: In this trial concurrent IPV appeared to interfere with the anti-PRP response to DTaP/Hib vaccine, suggesting that introduction of new vaccines may require evaluation of immune responses to all concurrently administered vaccines.

The discriminative stimulus properties of LY233708, a selective serotonin reuptake inhibitor, in the pigeon.

RATIONALE: Understanding the contribution of the various serotonin (5-HT) receptor subtypes to the behavioral effects of selective serotonin reuptake inhibitors (SSRIs) may contribute to the discovery of increasingly effective drugs for the treatment of conditions such as depression, panic and obsessive-compulsive disorders. OBJECTIVES: A drug discrimination procedure was used to determine whether the administration of an SSRI was associated with a specific interoceptive stimulus cue and to what extent that cue was related to activation of the 5-HT(1A) receptor. METHOD: Pigeons were trained to discriminate 20 mg/kg of the short acting, SSRI, LY233708 dihydrochloride dihydrate [(-)-cis-1-(6-chloro-1,2,3,4- tetrahydro-1-methyl-2-naphthalenyl)piperazine] from saline. RESULTS: LY233708 induced a specific, dose-related stimulus cue. The SSRIs, fluoxetine and citalopram, induced dose-related responding on the LY233708-associated key. In contrast, nisoxetine, a selective norepinephrine uptake inhibitor, induced responding on the saline-associated key. The prototypical 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-(2-di-n-propylamino)tetralin] substituted for LY233708. This generalization was blocked by the selective 5-HT(1A) antagonist, WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide]. CONCLUSION: These data demonstrate that an SSRI can induce a specific, stable discriminative stimulus that appears to involve activation of the 5-HT(1A) receptor in the pigeon.

[Measles outbreak in the province of Córdoba, Argentina, in 1998]. / Brote de sarampión en la provincia de Córdoba, Argentina, en 1998.

The World Health Organization had the global target of reducing reported measles incidence from pre-vaccination era in American countries by 1995, to later eliminate indigenous measles transmission. The countries that have given priority to measles control have substantially reduced morbidity and mortality. Despite that, measles has continued occurring in epidemic outbreaks. This paper describes and analyses the outbreak occurred in Cordoba province, Argentina, in 1998. Out of 195 serum samples analysed from suspected cases, 28 (14.4%) were confirmed as measles by laboratory diagnosis. Of them, 25.0% occurred among vaccinated persons, 39.3% among unvaccinated ones, and 35.7% in individuals without reported vaccine status. The highest measles incidence was in the group aged 20-29 years old (60.7%), followed by the pre-school age group (1-4 years old) (21.4%), the infants under one year of age (14.3%) and finally 3.5% in the group older than 30 years old. These findings suggest a change in measles epidemiology with respect to the pre-vaccine era. The ability to prevent the next epidemic outbreaks will depend on the efficacy to prevent the accumulation of susceptible individuals and the maintenance of high measles vaccine coverage levels.

Brote de sarampión en la provincia de Córdoba, Argentina, en 1998 / Measles outbreak in the province of Córdoba, Argentina, in 1998

The World Health Organization had the global target of reducing reported measles incidence from pre-vaccination era in American countries by 1995, to later eliminate indigenous measles transmission. The countries that have given priority to measles control have substantially reduced morbidity and mortality. Despite that, measles has continued occurring in epidemic outbreaks. This paper describes and analyses the outbreak occurred in Cordoba province, Argentina, in 1998. Out of 195 serum samples analysed from suspected cases, 28 (14.4) were confirmed as measles by laboratory diagnosis. Of them, 25.0 occurred among vaccinated persons, 39.3 among unvaccinated ones, and 35.7 in individuals without reported vaccine status. The highest measles incidence was in the group aged 20-29 years old (60.7), followed by the pre-school age group (1-4 years old) (21.4), the infants under one year of age (14.3) and finally 3.5 in the group older than 30 years old. These findings suggest a change in measles epidemiology with respect to the pre-vaccine era. The ability to prevent the next epidemic outbreaks will depend on the efficacy to prevent the accumulation of susceptible individuals and the maintenance of high measles vaccine coverage levels.(AU)

Brote de sarampión en la provincia de Córdoba, Argentina, en 1998 / Measles outbreak in the province of Córdoba, Argentina, in 1998

The World Health Organization had the global target of reducing reported measles incidence from pre-vaccination era in American countries by 1995, to later eliminate indigenous measles transmission. The countries that have given priority to measles control have substantially reduced morbidity and mortality. Despite that, measles has continued occurring in epidemic outbreaks. This paper describes and analyses the outbreak occurred in Cordoba province, Argentina, in 1998. Out of 195 serum samples analysed from suspected cases, 28 (14.4) were confirmed as measles by laboratory diagnosis. Of them, 25.0 occurred among vaccinated persons, 39.3 among unvaccinated ones, and 35.7 in individuals without reported vaccine status. The highest measles incidence was in the group aged 20-29 years old (60.7), followed by the pre-school age group (1-4 years old) (21.4), the infants under one year of age (14.3) and finally 3.5 in the group older than 30 years old. These findings suggest a change in measles epidemiology with respect to the pre-vaccine era. The ability to prevent the next epidemic outbreaks will depend on the efficacy to prevent the accumulation of susceptible individuals and the maintenance of high measles vaccine coverage levels.

A case-control study of risk factors for Haemophilus influenzae type B disease in Navajo children.

To understand the potential risk factors and protective factors for invasive Haemophilus influenzae type b (Hib) disease, we conducted a case-control study among Navajo children less than two years of age resident on the Navajo Nation. We analyzed household interview data for 60 cases that occurred between August 1988 and February 1991, and for 116 controls matched by age, gender, and geographic location. The Hib vaccine recipients were excluded from the analyses. Conditional logistic regression models were fit to examine many variables relating to social and environmental conditions. Risk factors determined to be important were never breast fed (odds ratio [OR] = 3.55, 95% confidence interval [CI] = 1.52, 8.26), shared care with more than one child less than two years of age (OR = 2.32, 95% CI = 0.91, 5.96); wood heating (OR = 2.14, 95% CI = 0.91, 5.05); rodents in the home (OR = 8.18, 95% CI = 0.83, 80.7); and any livestock near the home (OR = 2.18, 95% CI = 0.94, 5.04).

Brote de sarampión en la provincia de Córdoba, Argentina, en 1998. / [Measles outbreak in the province of Córdoba, Argentina, in 1998]

The World Health Organization had the global target of reducing reported measles incidence from pre-vaccination era in American countries by 1995, to later eliminate indigenous measles transmission. The countries that have given priority to measles control have substantially reduced morbidity and mortality. Despite that, measles has continued occurring in epidemic outbreaks. This paper describes and analyses the outbreak occurred in Cordoba province, Argentina, in 1998. Out of 195 serum samples analysed from suspected cases, 28 (14.4

) were confirmed as measles by laboratory diagnosis. Of them, 25.0

occurred among vaccinated persons, 39.3

among unvaccinated ones, and 35.7

in individuals without reported vaccine status. The highest measles incidence was in the group aged 20-29 years old (60.7

), followed by the pre-school age group (1-4 years old) (21.4

), the infants under one year of age (14.3

) and finally 3.5

in the group older than 30 years old. These findings suggest a change in measles epidemiology with respect to the pre-vaccine era. The ability to prevent the next epidemic outbreaks will depend on the efficacy to prevent the accumulation of susceptible individuals and the maintenance of high measles vaccine coverage levels.

Selective serotonin reuptake inhibitors potentiate 8-OH-DPAT-induced stimulus control in the pigeon.

The effects of two selective serotonin reuptake inhibitors, fluoxetine and citalopram, and a nonselective monoamine reuptake inhibitor, imipramine, were characterized in pigeons that had been trained to discriminate 0.64 mg/kg of 8-hydroxy-(2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist, from saline. Neither fluoxetine, citalopram, nor imipramine generalized to the 8-OH-DPAT-induced stimulus cue. However, when administered in addition to 8-OH-DPAT, both fluoxetine (10 mg/kg) and citalopram (10 mg/kg) lowered the ED50 for generalization of 8-OH-DPAT from 0.16 mg/kg (8-OH-DPAT by itself) to 0.05 mg/kg (fluoxetine + 8-OH-DPAT) and 0.06 mg/kg (citalopram + 8-OH-DPAT). Under similar conditions, imipramine (1 mg/kg) had no effect on the generalization curve for 8-OH-DPAT. The data support the hypothesis that activation of the 5-HT1A receptor may be relevant to the mechanism of action of serotonin reuptake inhibitors.

Analysis of intercurrent human immunodeficiency virus type 1 infections in phase I and II trials of candidate AIDS vaccines. AIDS Vaccine Evaluation Group, and the Correlates of HIV Immune Protection Group.

Among 2099 uninfected subjects in phase I and II trials of candidate AIDS vaccines, 23 were diagnosed with intercurrent human immunodeficiency virus type 1 (HIV-1) infection. High-risk sexual exposures accounted for 17 infections, and intravenous drug use accounted for 6. Four subjects received placebo, 13 received a complete immunization schedule (> or = 3 injections), and 6 were partially immunized (< or = 2 injections). There was no significant difference between vaccine recipients and control groups in incidence of HIV-1 infection, virus load, CD4 lymphocyte count, or V3 loop amino acid sequence. In summary, 19 vaccinated subjects acquired HIV-1 infection during phase I and II trials, indicating that immunization with the products described is < 100% effective in preventing or rapidly clearing infection. Laboratory analysis suggested that vaccine-induced immune responses did not significantly affect the genotypic or phenotypic characteristics of transmitted virus or the early clinical course of HIV-1 infection.

Differentiation of 5-HT1A receptor ligands by drug discrimination.

Pigeons were trained to discriminate 0.64 mg/kg (high dose) of 8-OH-DPAT (8-hydroxy-(2-di-n-propylamino)tetralin) from saline or were retrained to discriminate 0.16 mg/kg (low dose) of 8-OH-DPAT from saline. This resulted in a decrease of the ED50 for recognition of the 8-OH-DPAT cue from 0.14 to 0.04 mg/kg. Partial agonists for the 5-HT1A receptor (e.g., buspirone) were generalized fully in the low dose condition, but only partially in the high dose condition. Full antagonists, such as N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635), antagonized the 8-OH-DPAT cue in both groups without producing generalization in either group. (-)-Pindolol produced full generalization in the low dose group, but antagonized the high dose stimulus cue. The behavioral effects of other compounds with 5-HT1A receptor activities (4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-pyridinyl-benz ami de hydrochloride (p-MPPI): (-)-1-(1H-indol-4-yloxy)-3-(cyclohexylamino)-2-propanol maleate ((-)-LY206130); racemic pindolol and idazoxan) also differed between groups. Comparing results obtained using differing training doses in the drug discrimination paradigm simplifies determination of the full agonist, partial agonist, or antagonist properties of compounds.

Effects of a 5-HT1A receptor agonist on acute and delayed cyclophosphamide-induced vomiting.

LY228729 [(-)-4(dipropylamino)-1,3,4,5-tetrahydrobenz-[c,d]indole-6-carboxa mide]], an agonist at the 5-HT1A subtype of 5-HT receptor, was studied as an antiemetic in pigeons dosed with a highly emetic oncolytic agent, cyclophosphamide. An intramuscular injection of 0.32 mg/kg of LY228729 administered 15 min prior to the intravenous injection of 200 mg/kg of cyclophosphamide totally prevented the acute emetic response induced by cyclophosphamide. When used as a rescue therapy in a separate group of pigeons, LY228729 (0.32 mg/kg, i.m.) prevented further emetic episodes when it was administered after vomiting had already been induced by cyclophosphamide. Injections of LY228729 given at intervals over the next 2 d also attenuated the delayed emetic response induced by cyclophosphamide. LY228729 appears to be a broad spectrum antiemetic agent that is effective against the anticipatory, the acute and the delayed stages of emesis induced by oncolytic agents.