Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease.

The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.

An Update on Autophagy as a Target in the Treatment of Alzheimer's Disease.

Proteostasis is crucial for the maintenance and proper operation of cells. Under typical circumstances, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are used to clean out undesired, damaged, misfolded, or aggregated proteins. Any dysregulation in the above-mentioned pathways leads to neurodegeneration. One of the most renowned neurodegenerative disorders is AD. This condition is more prevalent in senior people and is frequently linked to dementia, progressive memory loss, and cognitive function decline, which further contributes to cholinergic neuron degradation and synaptic plasticity loss. Extracellular accumulation of amyloid beta plaques and the intraneuronal deposition of misfolded neurofibrillary tangles are two prime pathological reasons for AD. At present, there is no treatment for AD. All that remains available is the symptomatic treatment of this disease. Autophagy is the major mechanism by which the cells degrade the protein aggregates. Deposited immature autophagic vacuoles (AVs) in AD brains suggest interruption of a person's normal autophagy process. This review has briefly covered various forms and mechanisms of autophagy. Furthermore, the discussion in the article is supported by different ways and mechanisms via which autophagy can be stimulated in a beneficial way and can emerge as a novel target in the treatment of various metabolic CNS related disorders. In the current review article, the mTOR-dependent ones are PI3K/Akt/TSC/mTOR, AMPK/TSC/mTOR, and Rag/mTOR pathways and mTOR-independent ones which include Ca2+/calpain, inositol-dependent, cAMP/EPAC/PLC, and JNK1/Beclin-1/PI3K pathways have been discussed in details. The article sheds light on drugs which are validated with details in tabular form from recent updates in clinical trials.

The roles of HDAC with IMPDH and mTOR with JAK as future targets in the treatment of rheumatoid arthritis with combination therapy.

Various studies have shown that cytokines are important regulators in rheumatoid arthritis (RA). In synovial inflammation alteration of the enzyme HDAC, IMPDH enzyme, mTOR pathway, and JAK pathway increase cytokine level. These increased cytokine levels are responsible for the inflammation in RA. Inflammation is a physiological and normal reaction of the immune system against dangerous stimuli such as injury and infection. The cytokine-based approach improves the treatment of RA. To reach this goal, various researchers and scientists are working more aggressively by using a combination approach. The present review of combination therapy provides essential evidence about the possible synergistic effect of combinatorial agents. We have focused on the effects of HDAC inhibitor with IMPDH inhibitor and mTOR inhibitor with JAK inhibitor in combination for the treatment of RA. Combining various targeted strategies can be helpful for the treatment of RA.

Critical Strategies for Drug Precipitation Inhibition: A Review with the Focus on Poorly Soluble Drugs.

An oral route for drug administration is a more suitable route because of its ease of administration, pain avoidance, patient compliance, accommodation of various types of drug molecules, etc. But there are many factors affecting the oral absorption of the drugs. The main factor associated with oral absorption is drug solubility. Many new chemical molecules are poorly soluble in nature and can be included in BCS classes II and IV. For the administration of these drugs through the oral route, it was found that solubility is the rate limiting step. The low solubility of these drugs tends to cause precipitation in the gastrointestinaltract (GIT), affecting their bioavailability. Drug precipitation may be triggered by many factors such as insolubility of the drug in co-solvent, drug-excipient interactions, physiochemical properties of the drug, sudden change in the pH of the environment, incompatibility with the surfactant, etc. Precipitation of a drug may occur in two stages, formation of nucleation and crystal growth. To overcome precipitation, there are many strategies such as the use of polymers, the addition of surfactants, modulating drug loading and solubilizing capacity, change in the pH of the environment, etc. In this review, the causes of precipitation and diverse strategies of precipitation inhibition are critically reviewed.

Plants with potential anti-ulcerogenic activity and possible mechanism of actions based on their phyto-constitutional profile.

Gastric ulcer, the most common disorder of the digestive tract is formed due to an imbalance between acid and mucus content of the stomach. However, the currently used western therapeutic regimens have many drawbacks like adverse effects, recurrence of gastric ulcers, are expensive, and also, may have interactions with other drugs. Hence, there is a need for effective alternative therapy. Medicinal herbs have been used since ancient times to treat several diseases and are also evidenced to be effective against gastric ulcers. It is also evident that medicinal herbs have been proved to be equally effective or superior as compared to the existing synthetic medicines. In this review, five herbs have been taken into consideration and assumed to be effective against gastric ulcers. Abrus mollis, Korean Thistle (Cirsium japonicum var. maackii), Astralagus complanatus Bunge, Bauhinia monandra, and Embelia ribes Burm f. are the herbs whose data is been collected and reviewed for their potential gastro-protective action. Although, their side effects and toxicity profile need to be further evaluated. Hence, the purpose of this review is to gather evidence of these five medicinal herbs and their probable mechanism of action against gastric ulcers based on their phyto-constitutional profile.

Combinatory Approaches Targeting Cognitive Impairments and Memory Enhancement: A Review.

The objective of this paper is to look at how natural medicines can improve cognition and memory when used with sildenafil, a popular erectile dysfunction medicine that also has nootropic properties. Newer treatment strategies to treat the early stages of these diseases need to be developed. Multiple factors lead to complex pathophysiological conditions, which are responsible for various long-term complications. In this review, a combination of treatments targeting these pathologies is discussed. These combinations may help manage early and later phases of cognitive impairments. The purpose of this article is to discuss a link between these pathologies and a combinational approach with the objective of considering newer therapeutic strategies in the treatment of cognitive impairments. The natural drugs and their ingredients play a major role in the management of disease progression. Additionally, their combination with sildenafil allows for more efficacy and better response. Studies showing the effectiveness of natural drugs and sildenafil are mentioned, and how these combinations could be beneficial for the treatment of cognitive impairments and amnesia are summarised. Furthermore, preclinical and clinical trials are required to explore the medicinal potential of these drug combinations.

Metoclopramide as a Potential Antipsychotic Against Long-Term Methionine Exposure in Zebrafish.

Methionine (MET) contributes to brain function and is required for proper functioning of the central nervous system. However, exceptionally high levels of MET and its metabolites in plasma have been found to be toxic and can lead to cell alterations. Long-term exposure to MET has been shown to mimic psychotic symptoms in schizophrenic patients and rodents. The present study evaluated behavioral and neurochemical effects of long-term exposure to MET in zebrafish. Five groups of zebrafish were exposed to MET at a concentration of 4.5 mM for 7 days, along with acute exposure to 25 µM of clozapine and 750, 1000, and 1250 µM of metoclopramide. In contrast, the normal group was exposed to only water and dimethyl sulfoxide. After the treatment, social interaction, anxiety, memory, and locomotion of zebrafish and serotonin levels in zebrafish brains were evaluated. Our results showed that metoclopramide was not only beneficial in improving MET-induced cognitive impairment but it also prevented social withdrawal in zebrafish exposed to MET. In addition, metoclopramide reversed anxiety-like behavior, as indicated by significant changes in locomotion activity. Despite slight changes in serotonin levels in the zebrafish brain, an in vitro serotonin assay failed to demonstrate significant differences between the disease control, normal, and two treatment groups. Finally, results from the study showed that repeated administration of MET induced schizophrenia-like symptoms, although metoclopramide ameliorated the MET-mediated negative symptoms and cognitive deficits in zebrafish. Overall, our findings suggest a new perspective to further explore the antipsychotic properties of metoclopramide.

Update on Oxytocin, Phosphodiesterase, Neurokinin, Glycine as a Therapeutic Approach in the Treatment of Schizophrenia.

BACKGROUND: Schizophrenia is a chronic psychiatric disorder characterized by disrupted thoughts, perception, mood, and behavior. It has a heterogeneous genetic and neurobiological background and affects about 0.5-1% of the adult population worldwide. Herein, we review the current approaches and advances in schizophrenia. The potential therapeutic compounds for the treatment of schizophrenia act on the oxytocin receptor, phosphodiesterase system, neurokinin receptor, and glycine transport 1 receptor. Therefore, this article provides an update on the pharmacology of different receptors in addition to the dopaminergic system. These findings would guide the readers on novel targets for schizophrenia with the potential to be therapeutic agents in the future. OBJECTIVE: To provide the researchers an update on the emerging role of oxytocin, phosphodiesterase, neurokinin, and glycine which can be explored as potential pharmacotherapeutic targets in the treatment of schizophrenia. METHODS: An extensive literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: schizophrenia, novel receptors, oxytocin, phosphodiesterase, neurokinin, and glycine. Furthermore, to provide insights into newer drug treatments for Schizophrenia, Furthermore, Clinicaltrials.gov website was searched for newer receptor-based drugs. RESULTS: Current literature supported by preclinical and clinical provides substantial evidence that oxytocin, phosphodiesterase, neurokinin, and glycine play a crucial role in Schizophrenia. CONCLUSION: Our findings indicate that though multiple antipsychotic drugs are prescribed to treat schizophrenia, novel approaches and/or mechanisms are plausible. Moreover, sensitive and specific diagnostic tools and safe and effective interventions, including novel therapeutic agents, are required to yield substantially improved future outcomes.

Combinational Approaches Targeting Various Aspects Involved in Intestinal Barrier Dysfunction-Induced Anxiety.

Anxiety disorder is one of the most prevalent psychiatric disorders. The high prevalence of comorbid gastrointestinal disorders and anxiety, as well as various limitations in current therapy, have necessitated the search for alternative techniques. The Gut-Brain Axis is the connecting link between the gut and the brain. One of the reasons for the Gut-Brain Axis malfunction resulting in HPA axis stimulation and anxiety is intestinal barrier dysfunction. Gut microorganisms, lipopolysaccharides, and other factors can stimulate the disruption of this intestinal barrier. Tight junction proteins, the epithelial barrier, the mucosal membrane, the Toll-like receptor/Myeloid differentiation factor 88 pathway, the activated immune system, and the HPA axis could all be potential targets for anxiety caused by intestinal barrier disruption. Quercetin and Rebamipide, Berberine and Agomelatine, Angiotensin II receptor type 1 blockers, and Lubiprostone can act on these targets to provide an anxiolytic effect.

An update on novel therapeutic intervention in Rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder that is slow progressive destruction of the joints and is caused by autoantibodies that target a variety of organs thereby leading to auto-destruction. Patients diagnosed with RA develop deformity of joints and show gradual functional impairment if they do not receive treatment within the desired timeline. The availability of biological treatments and the introduction of treat-to-target regimens have dramatically enhanced the outcome for patients treated with RA conditions. Nevertheless, there is still attention required for RA because patients do not respond adequately to currently available treatment regimens. Over the past few decades, newer therapy methods are evolving to better understand the in-depth literature behind the actual cause of RA. Thus, getting an insight into the importance of RA there is a need for a shift in the existing treatment. This article focuses on a comprehensive review of the therapeutic potential of newer targets such as Janus Kinase-signal transducer and activator of transcription pathway, Granulocyte macrophage-colony stimulating factor, Bruton's Tyrosine Kinase Pathway, Phosphoinositide-3-kinase Pathway, Dendritic cells, Neuropathway, Receptor activator of nuclearfactor-kappa-Β ligand (RANKL) Inhibitors, Mesenchymal Stem Cells and Synovial Anatomy emphasizing on Synovial fibroblasts Myeloid Cells which have been summarized. In addition, novel therapeutic targets such as proteins, small molecular metabolites, and epigenetics are described in this article. Cytokines, chemokines, and other protein targets are among the protein target. Prostaglandins, leukotrienes, platelet-activating factor, cannabinoids, and specific fatty acid amide hydrolase are all examples of small molecular metabolites. DNA, RNA, and Histone Modification are epigenetic targets. Furthermore, the article provides an in-depth understanding of the exact mechanism in underlying pathophysiology in RA and thereby substantiating their evident therapeutic effect with ongoing clinical trials. Nevertheless, these newer targets would help to bring and paradigm shift in the treatment of this ancient autoimmune disorder.

Importance of Exploring N-Methyl-D-Aspartate (NMDA) as a Future Perspective Target in Depression.

Major depressive disorder (MDD) is a serious and complex mental illness. Currently, many antidepressants are available in the market for the treatment of MDD. However, these agents are associated with side effects, which restricts their use. This warrants the development of advanced antidepressive medications with a novel mechanism of action or novel targets and with minimal adverse effects. The traditional neurobiological hypothesis of depression, the monoamine hypothesis, is unable to properly explain all the aspects of depressive conditions. In this review, we discuss novel approaches that could be used for the treatment of depression, including glutamatergic and serotonergic system modulation. The pathogenesis of depression is greatly affected by glutamatergic neurotransmission dysfunction. Previous investigations have shown that ketamine, an N-methyl-D-aspartate receptor antagonist, exerts fast and long-lasting antidepressant effects. Several glutamatergic modulators, such as esketamine, sarcosine, and others, have also shown potential antidepressant action in animal as well as clinical studies. Lastly, drugs that alter neurotransmission by NMDA receptors could open up new avenues for more effective treatment of depression. Besides, understanding the underlying mechanisms will aid in the development of novel and fast-acting antidepressant drugs in the future.

Use of In silico tools for screening buffers to overcome physical instability of Abatacept.

Rheumatoid arthritis is an autoimmune disorder. Abatacept (CTLA4-Ig) is used for the treatment of Rheumatoid arthritis. Abatacept is a monoclonal antibody. Monoclonal antibodies undergo chemical (e.g. oxidation, deamidation, hydrolysis) and physical (e.g. aggregation, unfolding) instabilities while handling and storage. Abatacept is also prone to aggregation. Stabilizing agents such as buffers are used to stabilize monoclonal antibodies. But, the selection of the appropriate buffer is a time-consuming process because after testing many buffers based on the analysis of the results the appropriate buffer is identified. To overcome this issue in the current study computational tools were utilized to virtually screen different buffers to select the appropriate buffer. Ligand binding is the principal mechanism of conformational stability of proteins. For the buffers as well ligand binding is the most common mechanism for enhancing the thermodynamic stability of proteins. Generally it is observed that by enhancing the thermodynamic stability there is reduction in the rate of aggregation of proteins. Buffer (ligand) binds to the native state of the protein preferentially; it results in stabilization of the protein, while in the case of denatured protein it has no impact. There are many studies conducted involving the proteins in buffer solutions but very limited information is available about the mechanism of protein-buffer interactions. In the current study ligand binding mechanism of protein - buffer interaction was studied using molecular docking. After the docking buffers were ranked according to their energy value. The lower energy scores represent better protein-buffer (ligand) binding affinity compared to high energy values. It was observed that Phosphate with a binding affinity of -107.9 kcal/mol was the buffer with the least binding energy followed by Citrate (-70.6 kcal/mol), Melglumine (-66.6 kcal/mol), Arginine (-64.5 kcal/mol), Glucono delta lactone (-62.6 kcal/mol), Sodium citrate (-56.5 kcal/mol), Tromethamine (-52.3 kcal/mol), Glycine HCl (-37.2 kcal/mol), Sulfuric acid (-37.7 kcal/mol), Ammonium acetate (-31.1 kcal/mol), Acetic acid (-30.7 kcal/mol). With lower binding energy higher is the affinity between the ligand and protein. So phosphate was identified as a buffer with the highest affinity with Abatacept.

Copper-lowering agents as an adjuvant in chemotherapy.

Copper is an important element essential for metabolism and normal human body function. Although it is an essential element, related imbalance leads to toxic effects. Studies have proved that there is an increase in copper level in cancer cells. Evidences suggest the link between increase in copper levels and progression of various types of cancers. Different strategies have been utilized to decrease the level of copper in various types of cancer cells. However, it was observed that cell machinery involved in copper homeostasis plays critical factor in lowering copper levels in cancer cells. The outcomes of many monotherapies consisting copper-lowering agents for the treatment of different types of cancers showed that the inhibition of single factor is not sufficient to inhibit the growth of cancer cells. The combination of copper-lowering agent with chemotherapeutic agent showed synergistic effect. Interestingly, the presence of copper-lowering agent in such combinations significantly improved the efficacy of chemotherapeutic agent. The present work has focused on the discussion of outcomes of studies involving anti-copper agent and chemotherapeutic agent and related future strategies.

Combinational Approaches Targeting Neurodegeneration, Oxidative Stress, and Inflammation in the Treatment of Diabetic Retinopathy.

Diabetic Retinopathy (DR) is one of the most severe ocular problems of diabetes. It is a microvascular complication that impairs the vision of diabetic individuals and can cause acquired blindness. Currently, available treatment options like laser therapy, vitrectomy, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and glucocorticoids help to reduce vision loss at advanced stages. In spite of the available therapies, patients with severe vision loss face difficulty in achieving the normal vision. There is a need for the development of newer treatment strategies to address the condition from the early stages. Multiple factors owing to complex pathophysiological events are responsible for this long-term complication. Neurodegeneration, inflammation, and oxidative stress are the three important factors associated with the development of DR. Oxidative stress is a major contributor to the onset and progression of DR. Pathological events like retinal neurodegeneration and inflammation damage the retina in the early stages of DR. Different combinations of treatments targeting these pathological events are discussed in the present review. The first combination discussed is citicoline and resveratrol and the second combination is duloxetine and N-acetyl cysteine (NAC). These combinations may help in the early stages of DR. CD5-2, and angiopoietin-2 inhibitors is the third combination and this combination may help to manage diabetic macular edema. The main purpose of this article is to discuss the link between these pathologies and the three combinational approaches with the objective of considerating newer therapeutic approaches in research related to DR treatment.

Mini review-vanadium-induced neurotoxicity and possible targets.

Vanadium, a transition metal, ubiquitous in nature is known to have therapeutic effect as well as toxic effect. It is known to possess antidiabetic, antitumor and antiparasitic activity. However, on long term exposure, it produces neurotoxicity which may result in memory impairment. The possible mechanism known to cause neurotoxicity suggested is oxidative stress and inflammation of neuronal cells. The present review has focused on discussing the role of protein P38 mitogen-activated protein kinase and oxidative stress as possible targets to treat vanadium-induced neurotoxicity.

Prominence of Oxidative Stress in the Management of Anti-tuberculosis Drugs Related Hepatotoxicity.

Advanced medical services and treatments are available for treating Tuberculosis. Related prevalence has increased in recent times. Unfortunately, the continuous consumption of related drugs is also known for inducing hepatotoxicity which is a critical condition and cannot be overlooked. The present review article has focused on the pathways causing these toxicities and also the role of enzyme CYP2E1, hepatic glutathione, Nrf2-ARE signaling pathway, and Membrane Permeability Transition as possible targets which may help in preventing the hepatotoxicity induced by the drugs used in the treatment of tuberculosis.

The effect of bupropion augmentation of minocycline in the treatment of depression.

The aim of the current study was to analyse the augmentation of minocycline with bupropion in treating depression. 'Saline' (10 ml/kg), 'minocycline per se' (25 mg/kg), 'minocycline per se' (50 mg/kg), 'bupropion per se' (5 mg/kg), 'bupropion per se' (10 mg/kg) and 'bupropion + minocycline' (5 mg/kg + 25 mg/kg each) were administered to mice via the intraperitoneal route. In the forced swim and tail suspension test, the immobility period was analysed after 30 min of the treatment. Monoamines like dopamine, norepinephrine and serotonin levels were analysed in brain areas such as the whole brain, hippocampus and cerebral cortex using an HPLC-fluorescence detector. Euthanasia of mice was performed 1 h after treatment. Comparison between the control group and combination therapy and other standard drug groups showed a significant decrease in immobility in both antidepressant animal models. The combination of bupropion and minocycline showed greater benefits with respect to a reduction in the immobility time period and enhancement of dopamine, serotonin, and norepinephrine levels in the cerebral cortex, hippocampus and the whole brain when compared to the monotherapy treated groups. Hence, the side effects may be reduced drastically through this combination by a reduction in the bupropion/minocycline dosage.

Potentiation of Antidepressant Effects of Agomelatine and Bupropion by Hesperidin in Mice.

Hesperidin, a well-known flavanone glycoside mostly found in citrus fruits, showed neuroprotective and antidepressant activity. Agomelatine, a melatonergic MT1/MT2 agonist and 5-HT2C receptor antagonist, exhibits good antidepressant efficacy. Bupropion has been widely used for the treatment of depression because of its dopamine and norepinephrine reuptake inhibition. The objective of present study was to assess the antidepressant effects of hesperidin combination with agomelatine or bupropion. Male Swiss Albino mice received treatment of saline, vehicle, 'hesperidin alone', 'agomelatine alone', hesperidin+agomelatine, 'bupropion alone', hesperidin+bupropion, and agomelatine+bupropion for 14 days. The immobility period was analysed 30 min after the treatment in forced swim and tail suspension tests. Dopamine and serotonin levels were analysed in hippocampus, cerebral cortex, and whole brain using HPLC with fluorescence detector. Hesperidin plus agomelatine treated group was better in terms of decrease in immobility period and increase in dopamine and serotonin levels when compared to their respective monotherapy treated groups.

Herbal approach in the treatment of pancytopenia.

Pancytopenia is a health condition in which there is a reduction in the amount of leucocytes, erythrocytes and thrombocytes. If more than one of the blood cells is low then the condition is called as bicytopenia. The pancytopenic condition is observed in treatment of diseased conditions like thalassemia and hepatitis C. Iatrogenically pancytopenia is caused by some antibiotics and anti-HCV drugs. Medical conditions like aplastic anaemia, lymphoma, copper deficiency, and so forth can also cause pancytopenia. Pancytopenia can in turn decrease the immunity of the person and thereby can be fatal. Current therapies for pancytopenia include bone marrow stimulant drugs, blood transfusion and bone marrow transplant. The current therapies are very excruciating and have long-term side-effects. Therefore, treating these condition using herbal drugs is very important. Herbs like wheatgrass, papaya leaves and garlic are effective in treating single lineage cytopenias. The present review is focused on the potential effects of natural herbs for the treatment of pancytopenia.

Evaluation of anxiolytic effects of aripiprazole and hydroxyzine as a combination in mice.

CONTEXT: Anxiety disorders are chronic, common, and often comorbid. There is an unmet need in its treatment. Aripiprazole and hydroxyzine are well-known therapeutic options used as monotherapy in clinics. They have different mechanisms and site of actions. AIM: The objective of the present study was to evaluate the anxiolytic effect of aripiprazole and hydroxyzine in combination. MATERIALS AND METHODS: Swiss albino mice (male) received treatment of 5% of Tween 80 in 0.9% saline (10 ml/kg; control group), "aripiprazole alone" (1 mg/kg), "hydroxyzine alone" (3 mg/kg), and aripiprazole (0.5 mg/kg) + hydroxyzine (1.5 mg/kg) through the intraperitoneal route. RESULTS: The in vivo outcomes (elevated plus maze, light/dark transition, and marble burying tests) of hydroxyzine monotherapy-treated group showed a significant anxiolytic activity. The combination-treated group was found to be better than control and aripiprazole-treated groups. The combination-treated group showed a significant increase in the level of serotonin in different brain regions as compared to aripiprazole-treated group but not better than the hydroxyzine group. The in vitro results were in compliance with the in vivo results. The combinational approach was found to be beneficial in anxiolytic treatment as compared to aripiprazole monotherapy. However, hydroxyzine showed better anxiolytic activity when compared to control, aripiprazole monotherapy, and combination groups. CONCLUSIONS: The anxiolytic effect of combination-treated group was found to be better than aripiprazole monotherapy and lesser than hydroxyzine monotherapy.