Serotonin Modulates Sensitivity to Reward and Negative Feedback in a Probabilistic Reversal Learning Task in Rats

Depressed patients show cognitive deficits that may depend on an abnormal reaction to positive and negative feedback. The precise neurochemical mechanisms responsible for such cognitive abnormalities have not yet been clearly characterized, although serotoninergic dysfunction is frequently associated with depression. In three experiments described here, we investigated the effects of different manipulations of central serotonin (5-hydroxytryptamine, 5-HT) levels in rats performing a probabilistic reversal learning task that measures response to feedback. Increasing or decreasing 5-HT tone differentially affected behavioral indices of cognitive flexibility (reversals completed), reward sensitivity (win-stay), and reaction to negative feedback (lose-shift). A single low dose of the selective serotonin reuptake inhibitor citalopram (1 mg/kg) resulted in fewer reversals completed and increased lose-shift behavior. By contrast, a single higher dose of citalopram (10 mg/kg) exerted the opposite effect on both measures. Repeated (5 mg/kg, daily, 7 days) and subchronic (10 mg/kg, b.i.d., 5 days) administration of citalopram increased the number of reversals completed by the animals and increased the frequency of win-stay behavior, whereas global 5-HT depletion had the opposite effect on both indices. These results show that boosting 5-HT neurotransmission decreases negative feedback sensitivity and increases reward (positive feedback) sensitivity, whereas reducing it has the opposite effect. However, these effects depend on the nature of the manipulation used: acute manipulations of the 5-HT system modulate negative feedback sensitivity, whereas long-lasting treatments specifically affect reward sensitivity. These results parallel some of the findings in humans on effects of 5-HT manipulations and are relevant to hypotheses of altered response to feedback in depression.     

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound.     

Effects of the Partial M1 Muscarinic Cholinergic Receptor Agonist CDD-0102A on Stereotyped Motor Behaviors and Reversal Learning in the BTBR Mouse Model of Autism

BackgroundAutism spectrum disorders (ASD) are a set of neurodevelopmental disorders marked by a lack of social interaction, restrictive interests, and repetitive behaviors. There is a paucity of pharmacological treatments to reduce core ASD symptoms. Various lines of evidence indicate that reduced brain muscarinic cholinergic receptor activity may contribute to an ASD phenotype.MethodsThe present experiments examined whether the partial M₁ muscarinic receptor agonist, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A), alleviates behavioral flexibility deficits and/or stereotyped motor behaviors in the BTBR mouse model of autism. Behavioral flexibility was tested using a reversal learning test. Stereotyped motor behaviors were measured by eliciting digging behavior after removal of nesting material in a home cage and by measuring repetitive grooming.ResultsCDD-0102A (0.2 and 0.6 mg/kg but not 1.2 mg/kg) injected prior to reversal learning attenuated a deficit in BTBR mice but did not affect performance in B6 mice. Acute CDD-0102A treatment (1.2 and 3 mg/kg) reduced self-grooming in BTBR mice and reduced digging behavior in B6 and BTBR mice. The M₁ muscarinic receptor antagonist VU0255035 (3 mg/kg) blocked the effect of CDD-0102A on grooming behavior. Chronic treatment with CDD-0102A (1.2 mg/kg) attenuated self-grooming and digging behavior in BTBR mice. Direct CDD-0102A infusions (1 µg) into the dorsal striatum reduced elevated digging behavior in BTBR mice. In contrast, CDD-0102A injections in the frontal cortex were not effective.ConclusionsThe results suggest that treatment with a partial M₁ muscarinic receptor agonist may reduce repetitive behaviors and restricted interests in autism in part by stimulating striatal M₁ muscarinic receptors.     

Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report

Our report of a patient with severe tardive dyskinesia (TD) who has been exposed to both typical antipsychotic and clozapine, olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD. Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.     

Nano-Encapsulation of Plitidepsin: In Vivo Pharmacokinetics,Biodistribution, and Efficacy in a Renal Xenograft Tumor Model

Purpose

Plitidepsin is an antineoplasic currently in clinical evaluation in a phase III trial in multiple myeloma (ADMYRE). Presently, the hydrophobic drug plitidepsin is formulated using Cremophor®, an adjuvant associated with unwanted hypersensitivity reactions. In search of alternatives, we developed and tested two nanoparticle-based formulations of plitidepsin, aiming to modify/improve drug biodistribution and efficacy.

Methods

Using nanoprecipitation, plitidepsin was loaded in polymer nanoparticles made of amphiphilic block copolymers (i.e. PEG-b-PBLG or PTMC-b-PGA). The pharmacokinetics, biodistribution and therapeutic efficacy was assessed using a xenograft renal cancer mouse model (MRI-H-121 xenograft) upon administration of the different plitidepsin formulations at maximum tolerated multiple doses (0.20 and 0.25 mg/kg for Cremophor® and copolymer formulations, respectively).

Results

High plitidepsin loading efficiencies were obtained for both copolymer formulations. Considering pharmacokinetics, PEG-b-PBLG formulation showed lower plasma clearance, associated with higher AUC and Cmax than Cremophor® or PTMC-b-PGA formulations. Additionally, the PEG-b-PBLG formulation presented lower liver and kidney accumulation compared with the other two formulations, associated with an equivalent tumor distribution. Regarding the anticancer activity, all formulations elicited similar efficacy profiles, as compared to the Cremophor® formulation, successfully reducing tumor growth rate.

Conclusions

Although the nanoparticle formulations present equivalent anticancer activity, compared to the Cremophor® formulation, they show improved biodistribution profiles, presenting novel tools for future plitidepsin-based therapies.     

Secretion, pain and sneezing induced by the application of capsaicin to the nasal mucosa in man.

1. Topical application of capsaicin to the human nasal mucosa induced a burning sensation and sneezing. A dose-dependent seromucous nasal secretion was also observed. Capsaicin (75 micrograms) was more potent than methacholine (50 mg) in producing nasal secretion, while topical histamine (200 micrograms), substance P (135 micrograms) and calcitonin gene-related peptide (36 micrograms) did not induce rhinorrhea. 2. Pretreatment with either topical ipratropium bromide, systemic dexchlorpheniramine or indomethacin did not influence the effects induced by capsaicin. Topical pretreatment with lidocaine inhibited the painful sensation but failed to block the rhinorrhea. Desensitization to the effects of capsaicin occurred following 4-5 subsequent applications, and full recovery was observed within 30-40 days. 3. It is proposed that the effects of capsaicin in human nasal mucosa are due to excitation of primary afferent neurones that (a) convey burning and painful sensation, (b) evoke a sneezing reflex and (c) induce nasal secretion by releasing transmitter(s) from their peripheral terminals.     

Dopamine D1-Like and D2-Like Receptors in the Dorsal Striatum Control Different Aspects of Attentional Performance in the Five-Choice Serial Reaction Time Task Under a Condition of Increased Activity of Corticostriatal Inputs

We investigated the interaction between the corticostriatal glutamatergic afferents and dopamine D₁-like and D₂-like receptors in the dorsomedial striatum (dm-STR) in attention and executive response control in the five-choice serial reaction time (5-CSRT) task. The competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) injected in the mPFC impaired accuracy and increased premature and perseverative responding, raising GLU, DA, and GABA release in the dm-STR. The D₁-like antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 injected in the dm-STR reversed the CPP-induced accuracy deficit but did not affect the increase in perseverative responding. In contrast, the D₂-like antagonist haloperidol injected in the dm-STR reduced the CPP-induced increase in perseverative responding but not the accuracy deficit. The different roles of dorsal striatal D₁-like and D₂-like receptor were further supported by the finding that activation of D₁-like receptor in the dm-STR by {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393 impaired accuracy but not perseverative responding while the D₂-like agonist quinpirole injected in the dm-STR increased perseverative responding but did not affect accuracy. These findings suggest that integration of cortical information by D₁-like receptors in the dm-STR is a key mechanism of the input selection process of attention while the integration of corticostriatal signals by D₂-like receptors preserves the ability to switch from one act/response to the next in a complex motor sequence, thus providing for behavioral flexibility.     

Amphiphilic Ionic Liquids Capable to Formulate Organized Systems in an Aqueous Solution,Designed by a Combination of Traditional Surfactants and Commercial Drugs

Pharmaceutical Research - The present review describes the state of the art in the conversion of pharmaceutically active ingredients (API) in amphiphilic Ionic Liquids (ILs) as alternative drug...     

In vitro — In vivo correlation of dissolution,a time scaling problem? Transformation of in vitro results to the in vivo situation,using theophylline as a practical example

Summary Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.     

Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065.

1. Endothelin-1 binds almost irreversibly to its receptors and causes prolonged vasoconstrictions. Here we have studied the reversal of established responses to ET-1 in vivo and in vitro by BQ-123, an ETA receptor-selective antagonist, and/or PD 145065, an ETA/ETB receptor non-selective antagonist. 2. In anaesthetized rats pretreated with hexamethonium, infusion of ET-1 (10(-11) mol kg-1 min-1) increased the mean arterial pressure (MAP) from 93 +/- 1.5 mmHg to 137 +/- 2.4 mmHg after 70 min (n = 29). While the ET-1 infusion was continued an additional infusion of BQ-123 caused a gradual dose-dependent reduction in the pressor effect of ET-1. For instance, after a 60 min infusion of BQ-123 (10(-8) mol kg-1 min-1) the MAP was decreased by 29.3 +/- 4.3 mmHg (n = 4). 3. PD 145065 was a much weaker antagonist of the established pressor effects of ET-1. At 10(-8) mol kg-1 min-1 it had no significant effect and even at 10(-7) mol kg-1 min-1 the elevated blood pressure was only reduced by 11.8 +/- 8.0 mmHg (n = 5) after 60 min. Co-infusion of BQ-123 and PD 145065 caused smaller reductions in the established response to ET-1 than infusion of BQ-123 alone. 4. Sustained contractions of rat aortic rings induced by ET-1 (3 x 10(-9) M) and mediated by ETA receptors were slowly reversed by addition of BQ-123 (10(-5) M) or PD 145065 (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats

Rationale Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing.Objective The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model.Methods The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug.Results Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED₅₀ for suppression of jaw movements divided by the ED₅₀ for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1–14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing.Conclusions On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.     

Cannabinoid Receptor Activation Prevents the Effects of Chronic Mild Stress on Emotional Learning and LTP in a Rat Model of Depression

Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1–21. The agonist WIN55,212-2 or vehicle were administered on days 19–21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.     

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning,but Ketamine Abolishes those Effects

Witnessing pain and distress in others can cause psychological trauma and increase odds of developing PTSD in the future, on exposure to another stressful event. However, the underlying synaptic process remains unknown. Here we report that mice exposed to a conspecific receiving electrical footshocks exhibited enhanced passive avoidance (PA) learning when trained 24 h after the exposure. The exposure activated neurons in the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) and altered synaptic transmission from dmPFC to BLA. It increased amplitude, slowed decay of NMDA receptor-mediated currents, and generated silent synapses. Administration of sub-anesthetic ketamine immediately after the exposure prevented the enhancement of PA learning and silent synapse formation. These findings suggest that ketamine can prevent pathophysiological consequences of psychological trauma.     

Investigation of the Skin Sensitizing Properties of 5 Osmolytic Prodrugs in a Weight-of-Evidence Assessment, Employing In Silico, In Vivo, and Read Across Analyses

The amino acid esters ethyl glycinate (EG), dl-α-tocopheryl-(mono-)betainate hydrochloride (TMB), dl-α-tocopheryl-(mono-)glycinate hydrochloride (TMG), dl-α-tocopheryl-(mono-)prolinate hydrochloride (TMP), and dl-α-tocopheryl-(mono-)sarcosinate hydrochloride (TMS) were previously shown to exert an osmoprotective function to human skin in vitro. Based on literature data, the parent compounds α-tocopherol (vitamin E) and the amino acids glycine, betaine (trimethylated glycine), proline, and sarcosine (N-methylated glycine) are not considered to be sensitizers. To investigate skin sensitizing properties of the esters, EG, TMG, and TMP were tested in the Local Lymph Node Assay (LLNA). Remaining esters were assessed by read across analysis considering structural similarities and mechanistic aspects. The LLNA results were consistent with in silico outcomes from ToxTree 2.5.0 indicative for protein binding; EG was negative; TMG and TMP were positive. Since TMB and TMS showed structural similarities to TMG and TMP and were also positive in ToxTree, it was concluded that both TMB and TMS can also be expected to have a skin sensitizing potential and therefore animal testing was waived.     

Quetiapine XR efficacy and tolerability as monotherapy and as adjunctive treatment to conventional antidepressants in the acute and maintenance treatment of major depressive disorder: a review of registration trials

Results from pivotal registration trials in major depressive disorder cohere with outcomes from effectiveness studies indicating that the majority of individuals receiving single-agent pharmacotherapy fail to achieve and sustain symptomatic remission. Several factors provided the impetus for this review: suboptimal efficacy with existing pharmacotherapy for major depressive disorder, quetiapine XR efficacy in the acute and maintenance treatment of bipolar depression, emerging pharmacodynamic evidence that quetiapine XR (and/or its metabolites) uniquely engages monoaminergic systems salient to symptom relief in depressive syndromes, the increasing use of second-generation antipsychotics in the treatment of major depressive disorder and the recent FDA review of quetiapine XR in major depressive disorder. Studies reviewed herein are pivotal registration trials that evaluated the acute and maintenance efficacy and tolerability of quetiapine XR (as monotherapy and as adjunctive treatment) in major depressive disorder. In addition, we also review recent investigations characterizing the pharmacodynamic effect of quetiapine's principal active metabolite, norquetiapine. All studies were obtained from AstraZeneca (Wilmington, DE, USA) and have been presented at national/international scientific meetings. Taken together, extant studies demonstrated that quetiapine XR (50 – 300 mg) provides rapid and sustained symptomatic improvement in the acute and maintenance treatment of major depressive disorder. Quetiapine XR may also offer advantages relative to duloxetine in time to onset of antidepressant action. The major limitations of quetiapine XR use in major depressive disorder relate to weight gain and disrupted glucose/lipid homeostasis as well as sedation/somnolence. Quetiapine XR has tolerability advantages compared with duloxetine on measures of sexual dysfunction. The data from the studies reviewed herein also indicate that quetiapine XR poses a low risk for extrapyramidal side effects in middle-aged and elderly individuals with major depressive disorder.     

In Vivo Microdialysis Sampling in the Bile,Blood, and Liver of Rats to Study the Disposition of Phenol

Methods for continuous in vivo sampling in the bile, blood, and liver extracellular fluid are described. These methods are based on microdialysis sampling in anesthetized rats. A new flow-through microdialysis probe is described for sampling bile while maintaining normal bile flow. All three sites are simultaneously and continuously sampled to provide concentration–time profiles at multiple sites in a single experimental animal. This technique is demonstrated by studying the hepatic metabolism and biliary excretion of phenol in rats. Following an i.v. infusion of phenol, the major hepatic metabolite was found to be phenyl-glucuronide. Hydroquinone and 2-glutathionyl–hydroquinone were also detected but at lower concentrations. A similar pattern of metabolites was found in the bile and blood. For all of the metabolites, bile concentrations are higher than liver concentrations, indicating that the metabolites are actively excreted into the bile.     

Evaluation of the Interaction and Drug Release from α,β-Polyaspartamide Derivatives to a Biomembrane Model

This Article reports on a comparative study on the ability of various polymers, containing hydrophilic and/or hydrophobic groups, to interact with a biomembrane model using the differential scanning calorimetry (DSC) technique. Multilamellar vesicles of mixed dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidic acid (DMPA) were chosen as a model of cell membranes. The investigated samples were a water soluble polymer, the α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and its derivatives partially functionalized with polyethylene glycol (PEG₂₀₀₀) to obtain PHEA-PEG₂₀₀₀, with hexadecylamine (C₁₆) to obtain PHEA-C₁₆, and with both compounds to obtain PHEA-PEG₂₀₀₀-C₁₆. These polymers are potential candidates to prepare drug delivery systems. In particular, some samples give rise to polymeric micelles able to entrap hydrophobic drugs in an aqueous medium. The migration of drug molecules from these micelles to DMPC/DMPA vesicles also has been evaluated by DSC analysis, by using ketoprofen as a model drug.     

In Vivo Evaluation of the Release of Zidovudine and Polystyrene Sulfonate from a Dual Intravaginal Bioadhesive Polymeric Device in the Pig Model

This study focused on determining the concentration of zidovudine (AZT) and polystyrene sulfonate (PSS) in the plasma and vaginal tissue of the large white pig from an intravaginal bioadhesive polymeric device (IBPD). Biocompatible polymers were compressed with AZT and PSS into caplet-shaped devices for insertion into the posterior fornix of the pig vagina. A total of 25 pigs were used in this study. Plasma was sampled from the jugular vein at various time points after insertion of the IBPD reaching 28 days. At day 28, the pigs were euthanized and vaginal tissue was removed and digested with subtilisin for AZT and PSS extraction. The mean concentration detected in vaginal tissue at day 28 was 1.214 ± 0.062 mg/mL for AZT and 1.400 ± 0.071 mg/mL for PSS. Plasma concentration was significantly lower for AZT (0.332 ± 0.014 mg/mL) and PSS (0.256 ± 0.013 mg/mL). This indicated higher retention of AZT and PSS within the vaginal tissue. Molecular mechanics simulations blueprinted polymer–drug–mucin force-field interactions and energies that explicated the spatial preference of AZT and PSS for the vaginal tissue. Histopathotoxicity studies revealed negative-to-mild foreign body events and results strongly suggest that the IBPD may be suitable for prolonged intravaginal drug delivery in preventing the transmission of sexually transmitted infections and HIV/AIDS.