Academic literature on the topic 'Hypotensive agents – Pharmacokinetics'

Abstract Background: Although complete remission rates for AML are near 70% with combination induction and consolidation chemotherapy, most patients will relapse and die from the disease or treatment complications. New agents with unique mechanisms are needed. One such class of therapeutics are fusion proteins consisting of protein synthesis inactivating peptide toxins fused to tumor cell selective ligands. DT388-IL3 is one such fusion protein. Rationale: In preclinical studies, DT388-IL3 was cytotoxic to the IL3 receptor expressing leukemia cell lines but not toxic to IL3 receptor negative cell lines. This agent was less toxic to normal progenitors and not toxic to early hematopoietic stem cells. The majority of AML progenitors overexpress IL3 receptors. Animal model work in mice bearing human leukemia cells has demonstrated anti-leukemia efficacy which is dose dependent with this agent. Toxicities in monkeys include vascular leak syndrome and pancytopenia observed only at the highest doses. The MTD in monkeys was estimated at 60mcg/kg/day. We report preliminary data on the use of DT388-IL3 fusion protein in humans from an ongoing phase I trial. Pharmacokinetics; clinical and immune response to this novel fusion protein are also being followed. Patients and Methods: Patients with refractory AML were eligible. The first dose level was qd M-W-F X six doses of DT388-IL3 at 4mcg/kg/day with dose escalation planned for subsequent patients. Patients with progression of disease or unacceptable study drug toxicity were to be removed from the study. Toxicity was graded according to NCI CTCAE version 3.0. Three patients have been treated with DT388-IL3. Serum samples were collected and will be assayed for anti-DT388-IL3 antibodies prior to and after treatment. Blood samples were obtained to measure circulating levels of active DT388-IL3 and its half life. Patient blasts were also collected prior to treatment for later analysis of expression of IL3 receptors. Result: Two patients tolerated the treatment schedule(of six doses) without any significant toxicities. Mild fever, headaches, nausea were noted. Both of these patients had progression of disease-one during treatment and one on day 15 bone marrow biospy. The above mentioned patients died secondary to disease complications at 2 weeks and 18 weeks after their last dose of the study agent respectively. DT388-IL3 levels on these two patients post infusion were below the the reliable detectable limits of the assay. The third patient became febrile and hypotensive after the first dose. The hypotension persisted and she did not receive any further doses. This patient is alive 5 weeks later with supportive care alone. DT388-IL3 levels following this patient’s dose are as follows: 2min post infusion 34.3ng/ml, 30min post infusion 1.9ng/ml, 60min post infusion 0.075ng/ml, 120min post infusion 0.003ng/ml, 240min post infusion undetectable. Conclusion: Preclinical/animal studies suggest that DT388-IL3 has anti-leukemia efficacy. Preliminary data from our ongoing phase I trial reveals minimal study agent related toxicity and no life threatening complications at this first dose level. Dose escalation is planned as per protocol.

PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.

Objective: To review the mechanism of action, mechanisms of resistance, in vitro activity, pharmacokinetics, pharmacodynamics, and clinical data for a novel aminoglycoside. Data sources: A PubMed search was performed from January 2006 to August 2019 using the following search terms: plazomicin and ACHN-490. Another search was conducted on clinicaltrials.gov for published clinical data. References from selected studies were also used to find additional literature. Study selection and data extraction: All English-language studies presenting original research ( in vitro, in vivo, pharmacokinetic, and clinical) were evaluated. Data synthesis: Plazomicin has in vitro activity against several multi-drug-resistant organisms, including carbapenem-resistant Enterobacteriaceae. It was Food and Drug Administration (FDA) approved to treat complicated urinary tract infections (cUTIs), including acute pyelonephritis, following phase II and III trials compared with levofloxacin and meropenem, respectively. Despite the FDA Black Box Warning for aminoglycoside class effects (nephrotoxicity, ototoxicity, neuromuscular blockade, and pregnancy risk), it exhibited a favorable safety profile with the most common adverse effects being decreased renal function (3.7%), diarrhea (2.3%), hypertension (2.3%), headache (1.3%), nausea (1.3%), vomiting (1.3%), and hypotension (1.0%) in the largest in-human trial. Relevance to patient care and clinical practice: Plazomicin will likely be used in the treatment of multi-drug-resistant cUTIs or in combination to treat serious carbapenem-resistant Enterobacteriaceae infections. Conclusions: Plazomicin appears poised to help fill the need for new agents to treat infections caused by multi-drug-resistant Enterobacteriaceae.

Endotracheal intubation, a common procedure in neonatal intensive care, results in distress and disturbs physiologic homeostasis in the newborn. Analgesics, sedatives, vagolytics, and/or muscle relaxants have the potential to blunt these adverse effects, reduce the duration of the procedure, and minimize the number of attempts necessary to intubate the neonate. The medical care team must understand efficacy, safety, and pharmacokinetic data for individual medications to select the optimal cocktail for each clinical situation. Although many units utilize morphine for analgesia, remifentanil has a superior pharmacokinetic profile and efficacy data. Because of hypotensive effects in preterm neonates, sedation with midazolam should be restricted to near-term and term neonates. A vagolytic, generally atropine, blunts bradycardia induced by vagal stimulation. A muscle relaxant improves procedural success when utilized by experienced practitioners; succinylcholine has an optimal pharmacokinetic profile, but potentially concerning adverse effects; rocuronium may be the agent of choice based on more robust safety data despite a relatively prolonged duration of action. In the absence of an absolute contraindication, neonates should receive analgesia with consideration of sedation, a vagolytic, and a muscle relaxant before endotracheal intubation. Neonatal units must develop protocols for premedication and optimize logistics to ensure safe and timely administration of appropriate agents.

Receptor-binding profiles of antipsychotics differ, with important implications for treatment efficacy and tolerability. Receptors implicated in clinical response and adverse effects include dopamine D2, serotonin 5HT1A and 5HT2A, as well as H1 histamine, M1 muscarinic and alpha1 adrenergic receptors. Varying receptor affinities can explain the clinical profile specific to each compound, including adverse events such as weight gain, metabolic disturbance, hypotension, hyperprolactinaemia and extrapyramidal symptoms.Receptor profiles also play a role when switching between antipsychotics. Consideration of the differences between agents being withdrawn and introduced can minimise adverse events and ensure efficacy is maintained. Using strategies such as cross-titration, the consequences of receptor upregulation, and amplified or muted treatment effects can be minimised. Pharmacokinetic profiles of the agents should also be considered, as withdrawing an agent with a long half-life may lead to hangover effects.In all patients, a pharmacological basis should be used to select agents with minimal drug-related adverse events. Patients at risk of metabolic syndrome, for example, may benefit from an agent with a low risk of weight gain, such as aripiprazole or ziprasidone, while agents associated with hypotension, such as clozapine, risperidone or quetiapine, should be avoided in elderly patients to reduce the risk of falls. The route of administration also impacts treatment decisions and appropriate use of co-medications needs to be considered carefully.By paying attention to the pharmacology of antipsychotic agents, physicians can balance good efficacy and a low incidence of adverse events, thereby optimising treatment for their patients with schizophrenia and bipolar disorder.

PurposeTo determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa).Patients and MethodsFifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m2/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m2).ResultsA dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m2(diarrhea, hypotension) occurring at an average 1-hour post-dose of ≥ 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at ≥ 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes.ConclusionThe maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m2. Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Objective: To review the literature and determine whether atypical antipsychotics should be used on an as-needed (prn) basis. Data Sources: Pertinent English-language literature dealing with atypical antipsychotics, typical antipsychotics, phamacokinetics, and prn dosing strategies was retrieved from a MEDLINE search (1960–1995). Data Extraction: Articles that discussed either pharmacokinetic parameters or the rationale for using antipsychotics on a prn basis. Data Synthesis: Administration of typical antipsychotics on a prn basis, either alone or in combination with scheduled antipsychotics, is a common practice. However, it has recently been recognized that the atypical agents, clozapine and risperidone, are also being prescribed for prn dosing. Clozapine has a sedative component that may provide a therapeutic benefit when prescribed prn, but it is also associated with dose-related seizures and orthostatic hypotension. Risperidone does not appear to exhibit sedation, except at very high doses. Conclusions: The risk-to-benefit ratio is not acceptable in using the atypical antipsychotic agents on a prn basis. There are documented safety and efficacy data that support the use of the typical antipsychotic agents such as chlorpromazine, or haloperidol in combination with lorazepam, on a prn basis. These latter choices are also more cost-effective.

Objective: To provide a comprehensive review of the pharmacokinetic and pharmacodynamic interactions between antipsychotics and antihypertensives and to provide recommendations for the selection of antihypertensives in patients receiving antipsychotic therapy. Data Sources: A MEDLINE search of the English-language literature was used to identify pertinent human and animal studies, reviews, and case reports. Study Selection: All available sources were reviewed. Data Extraction: Background information was obtained from comprehensive reviews. Individual case reports were assimilated, and pertinent data were extracted. Data Synthesis: Because hypertension is common in patients with psychiatric illness and antihypertensive agents are used for a multiplicity of indications, significant numbers of patients receive concurrent therapy with antihypertensives and antipsychotics. Many antipsychotics may block the antihypertensive efficacy of guanethidine and related drugs. The interaction between Clonidine and antipsychotics is defined less clearly. Limited data suggest possible additive hypotensive effects when chlorpromazine and methyldopa are given in combination. Increased plasma concentrations of thioridazine with a resultant increase in adverse effects have been reported when propranolol or pindolol are added to the regimen. A similar increase in chlorpromazine concentrations has been reported when propranolol was added. Although there are no reports documenting an interaction between a calcium-channel antagonist and an antipsychotic, the possible inhibition of oxidative metabolism of antipsychotics, additive calcium-blocking activity, and additive pharmacodynamic effects are theorized. Hypotension and postural syncope were reported in a patient given therapeutic dosages of chlorpromazine and Captopril, and in 2 patients when clozapine was added to enalapril therapy. Conclusions: No antipsychotic-antihypertensive combination is absolutely contraindicated, but no combination should be considered to be completely without risk. Antihypertensives with no centrally acting activity, such as diuretics, may be the least likely to result in adverse reactions. The combination of the beta-antagonists propranolol or pindolol with thioridazine or chlorpromazine should be avoided if possible. Scrupulous patient monitoring for attenuated or enhanced activity of either agent is essential whenever antipsychotics and antihypertensives are given concurrently.

3608^ Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3+3 dose-escalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n=9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n= 9) versus 33% low-dose (n=6)). A trend (p=0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.

Background: Cardiovascular complications are the leading cause of morbidity and mortality in the patients of end-stage renal disease leading to hemodialysis. Majority of these patients suffers from hypertension and adequate control of blood pressure is a challenge in these patients because of multifactorial etiology and complicated pharmacokinetic changes in these patients. The present study aims is to find out the best possible drug or combination of drugs that can provide better control of blood pressure and improve the quality of life of these patients.Methods: A retrospective study was carried out on the patients who attended the hemodialysis unit of Hakeem Abdul Hamid Centenary hospital from July 2015 to June 2016 (one year), data on antihypertensive drugs and blood pressure control (pre-dialysis and post-dialysis) were recorded and analyzed.Results: 68.75% patients on hemodialysis were suffering from hypertension and were on antihypertensive medication. A combination of Amlodipine and clonidine were the most frequently prescribed antihypertensive agents. Muscle cramps an acute rise in blood pressure and hypotension were the most frequently encountered intradialytic complications in these patients.Conclusions: Although a combination of amlodipine and clonidine was most frequently prescribed antihypertensive medication in these patients these drugs were associated with intradialytic complications like muscle cramps and hypotension. Amlodipine with beta-adrenoceptor blocker (metoprolol or bisoprolol) provided best control of blood pressure in these patients with least intradialytic complications.

Angiotensin-converting enzyme (ACE) inhibitors are some of the most commonly prescribed medications for hypertension. They are cited in many papers as the treatment most often recommended by guidelines and favoured over other antihypertensive drugs as first-line agents especially when other high-risk conditions are present, such as diabetic nephropathy. The development of captopril (CPT) was amongst the earliest successes of the revolutionary concept of structure-based drug design. Due to its relatively poor pharmacokinetic profile or short half-life of about 1 hour, the formulation of sustained-release microcapsule dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Currently, CPT is mainly administered in tablet form. One of the difficulties of CPT formulation has been reported to be its instability in aqueous solutions. CPT is characterized by a lack of a strong chromophore and, therefore, not able to absorb at the more useful UV–Vis region of the spectrum. For this reason, an accurate, simple, reproducible, and sensitive HPLC-ECD method was developed and validated for the determination of CPT in dosage forms. The method was successfully applied for the determination of CPT in commercial and developed formulations. Possible drug-excipient and excipient-excipient interactions were investigated prior to formulating CPT microcapsules because successful formulation of a stable and effective solid dosage form depends on careful selection of excipients. Nuclear magnetic resonance spectroscopy, Fourier transform infra-red spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used for the identification and purity testing of CPT and excipients. The studies revealed no thermal changes during stress testing of binary and whole mixtures which indicate absence of solid state interactions. There were no shifts, appearance and disappearance in the endothermic or exothermic peaks and on the change of other associated enthalpy values on thermal curves obtained with DSC method. Characteristic peaks for common functional groups in the FT-IR were present in all the mixtures indicating the absence of incompatibility. The techniques used in this study can be said to have been efficient in the characterization and evaluation of the drug and excipients. The technique of microencapsulation by oil-in-oil was used to prepare CPT microcapsules. The effects of polymer molecular weight, homogenizing speed on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared CPT microcapsules were examined. In order to decrease the complexity of the analysis and reduce cost response surface methodology using best polynomial equations was successfully used to quantify the effect of the formulation variables and develop an optimized formulation thereby minimizing the number of experimental trials. There was a burst effect during the first stage of dissolution. Scanning electron microscopy (SEM) results indicated that the initial burst effect observed in drug release could be attributed to dissolution of CPT crystals present at the surface or embedded in the superficial layer of the matrix. During the preparation of microcapsules, the drug might have been trapped near the surface of the microcapsules and or might have diffused quickly through the porous surface. The release kinetics of CPT from most formulations followed Fickian diffusion mechanism. SEM photographs showed that diffusion took place through pores at the surface of the microcapsules. The Kopcha model diffusion and erosion terms showed predominance of diffusion relative to swelling or erosion throughout the entire test period. Drug release mechanism was also confirmed by Makoid-Banakar and Korsmeyer-Peppas models exponents which further support diffusion release mechanism in most formulations. The models postulate that the total of drug release is a summation of a couple of mechanisms; burst release, relaxation induced controlled-release and diffusional release. Inspection of the 2D contour and 3D response surfaces allowed the determination of the geometrical nature of the surfaces and further providing results about the interaction of the different variables used in central composite design (CCD). The wide variation indicated that the factor combinations resulted in different drug release rates. Lagrange, canonical and mathematical modelling were used to determine the nature of the stationery point of the models. This represented the optimal variables or stationery points where there is interaction in the experimental space. It is difficult to understand the shape of a fitted response by mere inspection of the algebraic polynomial when there are many independent variables in the model. Canonical and Lagrange analyses facilitated the interpretation of the surface plots after a mathematical transformation of the original variables into new variables. In conclusion, these results suggest the potential application of Eudragit® / Methocel® microcapsules as suitable sustained-release drug delivery system for CPT.

This thesis describes in vitro and in vivo evaluation of a gastric retention formulation (GRF) developed at Oregon State University. The formulation was prepared from xanthan gum and locust bean gum as gelling agents and other formulation ingredients were added, then it was originally vacuum oven dried. The effect of freeze drying on GRF was studied in this research. Freeze dried GRF were evaluated for dissolution and drug release properties using hydrochlorothiazide as a model drug. The effect of storage of GRF inside hard gelatin capsules on rate of swelling of the capsule shell and release of GRF was also studied. Storage for up to 12 months had no effect on capsule shell swelling and release of GRF. Gastric residence time, pharmacokinetics and bioavailability of hydrochlorothiazide, a drug that has an absorption window limited to the upper small intestine, from two different sizes of gastric retention formulations (GRF) were evaluated in 12 healthy volunteers in both fed and fasted states, and compared to immediate release tablets. Extent of bioavailability of drug from the larger formulation in this study was comparable to IR tablets in both fed and fasted states. Deconvolved input functions data suggest that the GRF stayed in the stomach providing sustained drug input for 12-28 hours. Initial blood pressure lowering and side effects of hydrochlorothiazide from a gastric retention formulation were evaluated and compared to immediate release tablets in 10 subjects with stage I hypertension. Gastric retention formulations produced an average reduction in systolic blood pressure 3 mm Hg lower than IR tablets regardless of sequence of administration. GRF also produced less blood pressure fluctuation in most subjects than IR tablets. Most subjects reported fewer and less severe side effects with GRF than IR tablets.
Graduation date: 2004