Alza Research Articles

Survey the Microbial Load in the Tigris River in South of Baghdad City and Some of the Physiochemical Parameters

This study included an analysis of three stations (Al Dora, Al Za'franiya, and Arab Ejbur) chosen to study the Physiochemical and microorganism (Fungi and Bacteria) loud of the Tigris River in the southern section of Baghdad city. The result of this research shows that the highest temperature recorded in summer in Al Za'franiya was 37Co, while the lowest temperature recorded in winter in Al Dora was 9Co. and the value of pH recorded the highest in summer it was 7.9 in Arab Ejbur, and the lowest value was in winter 7.1 in Al Dora regions, While Total Organic Carbon (TOC) shows the highest values found in the summer was 6.7 Mg L-1in Al Za'franiya Samples, and the lowest values were 2.0 Mg L-1in Arab Ejbur during the winter. The more frequently isolated fungi were Aspergillus niger, and the lowest frequently was Chrysosporium was observed during the survey period. At the same time, Bacteriological analysis of water resources showed that Escherichia coli and Pseudomonas aeruginosa were more frequently isolated bacteria and the lowest frequently bacteria were Klebsiella ornithinolytica and Proteus mirabilis. Keywords. Fungi, Bacteria, Temperature, TOC, pH, Tigris River.

Electroencephalogram activity in attention-deficit hyperactivity disorder

ObjectiveThe aim of the study was to apply an evidence-based pharmacotherapy on different groups of attention-deficit hyperactivity disorder (ADHD) patients monitored by electroencephalogram (EEG) before and after 6 months of treatment and to estimate the prevalence of ADHD in a sample of Egyptian governorates (Kafr El Sheik and Menoufia neuropsychiatric clinics). It also aimed to detect the neurobiological basis of ADHD children using EEG.BackgroundADHD is one of the most commonly diagnosed and treated psychiatric disorders in childhood.Patients and methodA randomized, clinical trial was conducted on 30 children attending our neuropsychiatric outpatient clinic, screened from 255 children diagnostic through Diagnostic and statistical manual of mental disorders, 5th ed. and Kiddie-Schedule For Affective Disorders And Schizophrenia-Present And Lifetime Version. Psychiatry, Mental Health, (KSADS-PL) scale screening. Then the patients were divided into two equal groups. The first group received the drug Strattera (Eli Lilly Company) at a dose of (0.5: 1.2 mg/kg/day) only. The second group received Concerta (Alza Corporation) at a dose of (18 mg/day). Another 30 children are randomly allocated to control groups (30 children in each). Full history taking and complete clinical examination were done. KSADS-PL rating scale was assessed at baseline and then 6 months after treatment. EEG monitoring of children before and after treatment.ResultsIn this study we found that the score of the KSADS-PL rating scale was significantly decreased in ADHD patients after treatment in both pharmacotherapy groups. In addition, there was no significant difference in EEG between both ADHD children before and after treatment.ConclusionPharmacotherapy using drugs as concerta and stratera has beneficial effects in reducing ADHD symptom severity

Designing refugees\u2019 camps: temporary emergency solutions, or contemporary paradigms of incomplete urban citizenship? Insights from Al Za\u2019atari

Millions of people have been forcibly displaced around the world at an alarming rate. In 2018, approximately 70.8 million people (UNHCR 2018) were living in refugee camps. These camps are the most immediate response to the emergency. However, they have become more than a simple temporary solution, with refugees spending significantly longer than they should. Motivated largely by an economic rationale, the camps are often produced rapidly, cheaply and effectively to accommodate the largest possible number of shelters in the shortest time. The aim of this paper is to explore whether the concept of permanence should be embedded in the spatial configuration of a refugees’ camp, or whether the concept of transient and temporary community would better reflect the aspirations of the users. The Al Za’atari camp has been selected as a case study to explore the nexus between spatial configuration and social aspirations of the refugees’ community. Indeed, the findings revealed that the spatial configuration of the Al Za’atari camp reflects social fabric, habits and organization of the refugees’ community. This has occurred to the point that the camp has taken on the appearance of a sort of informal city. This study therefore suggests recommendations to support the design of spatial and architectural solutions that better meet the actual needs of the final users largely disregarded in the current emergency approach.

СУЧАСНИЙ СТАН СТВОРЕННЯ, ВИРОБНИЦТВА ТА ДОСЛІДЖЕННЯ ТАБЛЕТОВАНИХ ЛІКАРСЬКИХ ПРЕПАРАТІВ Повідомлення 25. Осмотичні системи вивільнення та доставки лікарських речовин: характеристика імплантаційних мініосмотичних, оральних та спеціальних типів осмотичних систем, їх застосування

Проведено огляд літературних джерел щодо характеристик та можливостей застосування імплантаційних мініосмотичних, оральних та спеціальних типів осмотичних систем вивільнення та доставки лікарських речовин, наведено приклади осмотичних систем, які зареєстровані на світовому ринку.

Development of nanoparticles for clinical use.

During recent years, there has been much interest in using nanoparticles (NPs) for delivery of therapeutic drugs or contrast agents. Many interesting in vitro and animal studies have been reported [1–3], and some NP-based products are already in clinical use. Iron-oxide containing NPs have been used as iron supplement or contrast agents in MRI for more than 20 years [4,5]. Albumin and liposomal-based products containing anticancer drugs have also been available for several years, and new NP-based products are in clinical trials [2,6]. The discrepancy between the large number of papers published about NPs and other drug candidates versus the few new drugs entering the market is heavily debated, and important discussions regarding what is needed to bring new products to the market have been published [6–9]. No doubt, there are many challenges to overcome before NPs may become common tools in clinical practice.

Open-label study to evaluate the efficacy and safety of extendedrelease hydromorphone in patients with chronic neuropathic pain

To assess the efficacy and safety of once-daily hydromorphone extended-release tablets (OROS [Alza Corporation, Mountain View, CA] hydromorphone ER) in patients with chronic neuropathic pain. Single-center, open-label, 12-week study. Opioid-tolerant patients with chronic neuropathic pain for $6 months (N = 30). Patients were converted from previous opioid therapy to OROS hydromorphone ER using a 5:1 morphine:hydromorphone equianalgesic dosing ratio, with an initial 50 percent reduction of the calculated equianalgesic dose, titrated every 3-4 days to adequate analgesia over 2 weeks. The primary efficacy measure was change from baseline to week 12 (end of study) on question #5 ("average pain") of the Brief Pain Inventory (BPI). Secondary measures included least pain, worst pain, current pain, and sleep interference on the BPI, as well as the Pain Quality Assessment Scale (PQAS) and patient global assessment of treatment satisfaction. Thirty patients were enrolled and received $1 dose of OROS hydromorphone ER, titrated to a final mean dose of 26.4 mg/d. Mean (SE) BPI change from baseline to end of study was -1.3 (0.59) for current pain (p < 0.05) and -1.8 (0.61) for worst pain (p < 0.01). Mean (SE) change from baseline was also significant for BPI scores for sleep interference (-1.7 [0.61]; p < 0.01) and PQAS scores (-24.8 [7.9], p < 0.01). The majority (81 percent) of patients were satisfied or very satisfied with treatment. The most common treatment-related adverse events were dizziness, headache, and nausea (two patients each). Patients with chronic neuropathic pain were safely and effectively converted to and maintained on OROS hydromorphone ER.

The pharmacology and formulation of paliperidone extended release

Paliperidone, or 9-hydroxyrisperidone (Invega®, Janssen, Antwerp, Belgium) is the major active metabolite of the atypical antipsychotic risperidone (Risperdal®, Janssen). It possesses a similar, though not identical, receptor pharmacology to the parent molecule. There are additional differences in terms of its predominant renal metabolism, lower protein binding and decreased inhibition of P-glycoprotein leading to decreased potential for drug–drug interactions. Paliperidone is approved as an extended release (ER) tablet based on an osmotic-controlled release oral Push–Pull™ delivery system (Oral Osmotic System, OROS®, Alza Corporation) for the treatment of schizophrenia. The ER formulation results in decreased fluctuations in plasma drug levels and allows for once-daily administration with initial tolerability that permits treatment initiation at a clinically effective dose without the need for titration. This achieves therapeutic levels rapidly and simplifies dosing regimens, leading to potentially better adherence and improved outcome. The present review focuses on the clinical implications of the pharmacology and formulation of paliperidone ER.

A review of paliperidone palmitate

Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available as a long-acting injection. Paliperidone (9-hydroxyrisperidone) is the active metabolite of risperidone, introduced initially as an extended release oral (ORal Osmotic System, OROS®, Alza Corporation) formulation (Invega®, Janssen). Paliperidone long-acting injection (PLAI) has now been developed as a suspension of paliperidone palmitate nanocrystals in an aqueous formulation (Invega Sustenna®, Xeplion®), administered monthly by intramuscular injection (deltoid or gluteal). Doses of PLAI can be expressed either in milligram equivalents (mg eq) of paliperidone palmitate or in milligrams of the active fraction of paliperidone. The recommended initiation regimen of 150 mg eq (234 mg) on day 1 and 100 mg eq (156 mg) on day 8 (both administered in the deltoid) achieves therapeutic blood levels rapidly and without the necessity of oral supplementation. No refrigeration or reconstitution prior to administration is required. PLAI has been shown in to be effective in controlling the acute symptoms of schizophrenia as well as delaying time to relapse. Safety and tolerability are comparable to RLAI with no new safety signals. Thus, PLAI may represent the rational development of RLAI with greater ease of use.

Professor William I. Higuchi: Teacher and Scientist

Professor William I. Higuchi: Teacher and Scientist

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence of alcohol

ABSTRACTObjective: The purpose of this study was to investigate the pharmacokinetic properties of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) in the presence of alcohol.* OROS is a registered trade name of ALZA Corporation, Mountain View, CA, USAResearch design and methods: In a single-centre, open-label, four-treatment, four-period, four-sequence, crossover study, two groups of 24 healthy subjects (fasted or fed) were randomised to receive four single doses of OROS hydromorphone 16 mg with solutions of either 0%, 4%, 20% or 40% alcohol, and with a naltrexone block.Main outcome measures: Plasma samples taken predose and at regular intervals up to 48 h after dosing were assayed for hydromorphone concentrations; a mixed-effect analysis of variance was done on log-transformed data. Bioequivalence was concluded if 90% confidence intervals of treatment mean ratios were between 80% and 125%.Results: Plasma hydromorphone concentrations were slightly higher after dosing with all alcohol treatments in both the fasted and fed subject groups. Median Tmax values were between 12 and 16 h and ranges were similar for all treatments. Cmax values increased after alcohol compared with no alcohol, with the increase slightly lower in the fed state. The greatest mean increase in Cmax observed was 1.3-fold in the fasted state and 1.1-fold in the fed state. Confidence intervals were within 80–125% for AUC but were slightly higher for Cmax.Conclusions: The pharmacokinetics of once-daily OROS hydromorphone were only minimally affected by alcohol, with no dose dumping of hydromorphone. The results indicate that the controlled-release properties of this formulation are maintained in the presence of alcohol.

Dapoxetine and Paroxetine for the Treatment of Premature Ejaculation

*Chemical and Pharmaceutical Development, Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ and †Clinical Pharmacology, and Experimental Medicine, ALZA Corporation, Mountain View, CA [email protected]

Providing Constant Analgesia with OROS ® Hydromorphone

OROS ® (ALZA Corporation, Mountain View, CA, USA) hydromorphone is a unique, once-daily formulation of the potent opioid hydromorphone that is being evaluated for the treatment of moderate-to-severe chronic pain. It uses a patented Push-Pull™ (ALZA Corporation) osmotic pump system to deliver hydromorphone in a continuous, monophasic manner over 24 hours, resulting in minimal peak-trough plasma-level fluctuation. Peak concentrations are achieved approximately 16 hours after administration, with levels equivalent to approximately 80% of peak attained within just 6 hours. The apparent half-life of OROS ® hydromorphone is 7–15 hours and steady-state concentrations are achieved after 2 days of dosing. The pharmacokinetics of OROS ® hydromorphone are dose proportional and are not affected significantly by environmental factors (pH or agitation) or the presence of food. These pharmacokinetic characteristics suggest that OROS ® hydromorphone is well suited to provide consistent, prolonged analgesia in patients with chronic pain.

Alza v Mylan: A Defence of ‘Teaching, Suggestion or Motivation’ and the Unresolved Question of Inherent Anticipation

<i>Alza v Mylan</i>: A Defence of ‘Teaching, Suggestion or Motivation’ and the Unresolved Question of Inherent Anticipation

Fentanyl HCl Patient-Controlled lontophoretic Transdermal System for the Management of Acute Postoperative Pain

To summarize the pharmaceutics, pharmacokinetics, development, and clinical application of IONSYS, the fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain. Clinical literature including both primary sources and review articles was accessed through a search of the MEDLINE databases (1980-October 2006). Key search terms included cutaneous analgesia, fentanyl, IONSYS, opioid, postoperative pain, and patient-controlled analgesia (PCA). Additional clinical trial and drug data were supplied by the manufacturer, the ALZA Corporation. Review articles, abstracts, and clinical studies related to patient-controlled iontophoretic transdermal fentanyl and postoperative pain management were analyzed. An evaluation of the research exploring IONSYS for the management of acute postoperative pain was conducted. Relevant information was then selected and is provided in this article. IONSYS is the first iontophoretic transdermal drug delivery system that utilizes low-level electrical energy to actively transport ionized fentanyl HCl through intact skin. Research has revealed that use of IONSYS for patients with acute postoperative pain is safe, effective, and well tolerated. Phase I-III trials have demonstrated an appropriate dosing range leading to effective analgesia, with minimal adverse effects. The analgesia provided by this system was found to be superior to that of analgesia placebo and equivalent to that of an intravenous morphine PCA. Data from clinical trials indicated that IONSYS is successful in controlling acute postoperative pain that circumvents the limitations of intravenous patient-controlled analgesia. The use of this system may serve as an alternative modality for the management of acute pain without increasing such adverse effects as bleeding, intravenous catheter infiltration, or manual pump malfunction.

Alza Corporation: An Illustration of Form Over Substance

Before merging with Johnson & Johnson in 2001, ALZA Pharmaceuticals Corporation was on the cutting edge of both drug delivery systems and creative financial arrangements. This paper explains the creation of two spin-off corporations by ALZA for the purpose of funding research and development (R&D) activities to be carried out primarily by and for the benefit of ALZA. The agreements between ALZA and its two spin-offs are outlined, the financial statement impact for ALZA is examined, and the disclosures made regarding the arrangements are critiqued. Results show that existing GAAP was circumvented to enhance revenue and net income over a period of eight years. Finally, the paper discusses the potential efficacy of a principles-based accounting standard in preventing the overstatement and circumvention of GAAP and argues for the continuing need for detailed guidance in the standard-setting process.

Evaluation of the bioequivalence of two transdermal fentanyl systems following single and repeat applications

ABSTRACTObjective: Transdermal delivery of fentanyl has potential benefits over slow-release morphine, being largely preferred by patients owing to the combination of effective pain relief, a good safety profile and easy, pain-free dosing. The new drug-in-adhesive Durogesic D-TRANS fentanyl Matrix Delivery System (DDTDF) has improved pharmaceutical characteristics and patient acceptability compared to the original Durogesic transdermal reservoir system (fentanyl transdermal reservoir), whilst still providing reliable and consistent delivery of fentanyl. The bioequivalence of these two systems was evaluated in two studies.* Durogesic and D-TRANS are registered trade marks of ALZA Corporation, Mountain View, CA, USA† Durogesic and D-TRANS are registered trade marks of ALZA Corporation, Mountain View, CA, USAResearch designs and methods: Eighty healthy volunteers received single (72 h) or multiple (288 h) applications of DDTDF and the transdermal reservoir system (100 µg/h) in two separate randomised, crossover bioequivalence studies. Bioequivalence was assessed by calculating the ratio of least squares means based on log-transformed data following single system application and at steady-state during the fourth application.Results: Both transdermal systems were bioequivalent with respect to all tested pharmacokinetic parameters. Inter-subject variability was comparable between the two systems and was greater than intra-subject variability. Transdermal delivery was well tolerated in both groups.Conclusions: The pharmacokinetic results demonstrate that DDTDF is bioequivalent to the original fentanyl transdermal reservoir system after single and multiple applications.

Alza's patent upheld

Alza's patent upheld

In Vitro and in Vivo Characterization of a Newly Developed Clonidine Transdermal Patch for Treatment of Attention Deficit Hyperactivity Disorder in Children

The aim of this study was to characterize a newly developed clonidine transdermal patch, KBD-transdermal therapeutic system (TTS), for the treatment of attention deficit hyperactivity disorder in children. In vitro release, penetration, and in vivo pharmacokinetics in rabbits were investigated. The smaller size of KBD-TTS (2.5 mg/2.5 cm2) showed a similar in vitro penetration to those of Catapres-TTS (2.5 mg/3.5 cm2, a clonidine transdermal patch used for the treatment of hypertension, Alza Corporation, U.S.A.). The transdermal penetration rate of clonidine was mainly controlled by the ethylene vinylacetate membrane used in the patch. The skin layer may be only a minor rate-limiting barrier after the topical skin layer at the dosing site is saturated with penetrating clonidine in the initial phase (0 to 12 h). A sensitive liquid chromatography-mass spectrometry method for the quantification of clonidine in rabbit plasma was developed using solid-phase extraction and gradient elution on LC combined with the selected-ion monitoring (SIM) mode. A single dose of clonidine transdermal patch (KBD-TTS) or Catapres-TTS was transdermally administered to rabbits (n=6 each) and removed after 168 h. The average half-life, Tmax, Cmax and Css values of clonidine in rabbits following administration of KBD-TTS were 19.27+/-4.68 h, 52.56+/-25.77 h, 27.39+/-9.03 ng/ml, and 25.82+/-9.34 ng/ml, similar to those of Catapres-TTS, respectively. The clonidine plasma concentration of KBD-TTS reached a steady state at 24 h through 168 h. The in vitro release rate of the clonidine from KBD-TTS significantly correlated with the in vivo absorption rate (p<0.001).

Dapoxetine

Dapoxetine [LY 210448], a selective serotonin reuptake inhibitor (SSRI), is structurally related to fluoxetine with antidepressant activity. Dapoxetine is the D-enantiomer of LY 243917 and is 3.5 times more potent as a serotonin reuptake inhibitor than the L-enantiomer. Dapoxetine was in phase I clinical trials in the US with Eli Lilly as an antidepressant, but no recent development has been reported for this indication. However, development is underway for the treatment of premature ejaculation, with phase III trials for this indication being completed in the US. The phase II trial for the treatment of premature ejaculation was conducted by PPD GenuPro, a subsidiary of PPD, which was established from a collaboration between Eli Lilly and PPD for the development of drugs to treat genitourinary disorders. Both Lilly and PPD had an option to re-license dapoxetine upon completion of phase II trials, but neither company exercised its option, and the rights remained with PPD GenuPro. In December 2003, PPD Inc. acquired from Eli Lilly and Co. the patents for dapoxetine for development in the field of genitourinary disorders. As part of the transaction, PPD and Lilly terminated their existing license agreement for dapoxetine. In December 2000, PPD GenuPro granted an exclusive, worldwide license for dapoxetine to ALZA Corporation, a wholly owned subsidiary of Johnson & Johnson. ALZA will be responsible for development, manufacturing and commercialisation of dapoxetine for urological indications, including premature ejaculation. It will make initial, milestone and royalty payments to PPD GenuPro, a portion of which will be paid to originator Eli Lilly. PPD Inc. received a milestone payment relating to the ongoing development of dapoxetine for premature ejaculation in July 2003. In December 2003, PPD and ALZA amended the dapoxetine license to allow PPD to receive a fixed-sum cash payment apon NDA approval. In return for this, ALZA will not have to make sales-based payments for a period of time following the approval of dapoxetine. If dapoxetine is approved by the US FDA for premature ejaculation, the drug will be marketed in the US by Ortho-McNeil Pharmaceutical, Inc. In December 2004, ALZA Corporation submitted a new drug application to the FDA for dapoxetine hydrochloride in the treatment of premature ejaculation. If approved by the FDA, dapoxetine hydrochloride will be marketed in the US by Ortho-McNeil Pharmaceutical, Inc. Johnson & Johnson plans to support the launch of dapoxetine for premature ejaculation with a 'responsible' direct-to-consumer advertising campaign. In May 2005, Johnson & Johnson presented data from two phase III trials involving dapoxetine for the treatment of premature ejaculation, during the 100th Annual Scientific Meeting of the American Urological Association (AUA-2005). Results on drug interactions and pharmacodynamics of dapoxetine were also presented during this meeting. Dapoxetine also appears to be a useful adjunct to morphine, lowering the threshold for analgesia, although the compound itself has negligible analgesic activity. In December 2003, PPD, Inc. acquired from Eli Lilly and Company the patents for dapoxetine for development in the field of genitourinary disorders. Under the terms of the agreement with Lilly, PPD will pay Lilly 65 million US dollars in cash. PPD will also pay Lilly a royalty on net sales of dapoxetine in excess of a certain threshold of annual net sales. As part of the transaction, PPD and Lilly terminated their existing license agreement for dapoxetine.

Topical Iontophoretic Delivery

At present, transdermal iontophoresis is used in the topical delivery of local anesthetics and anti-inflammatory agents. The treatment of hyperhidrosis and the diagnosis of cystic fibrosis are other clinical applications of iontophoresis. Also, a glucose-monitoring device has been developed utilizing the principle of reverse iontophoresis. Commercial iontophoretic systems that would continuously deliver therapeutic agents into the systemic circulation, corresponding to the passive transdermal patches, do not exist at the moment; however, Alza Corporation has announced that it has received an approvable letter from the US FDA regarding a new drug application for Ionsys®, an iontophoretic, fentanyl-containing, transdermal analgesic. There is currently a lot of interest in the potential of closed-loop systems, which not only sense changes in the concentration of the analyte in the skin and in the subdermal tissues, but also administer a drug in response to the fluctuating concentration/need. Thus, self-regulated or patient-regulated systems that allow medication to be administered at home would enable controlled therapy, while accounting for the individual needs of the patient. Predictable and controlled non-invasive drug delivery on the one hand, and putative adverse effects on the other, determine the success of topical iontophoretic systems and methods. The often unavoidable skin sensitization/irritation and other adverse reactions have to be related to the therapeutic benefit(s) of (bio)molecule administration; for example, the potential for skin irritation associated with pain control medication is quite different (in terms of acceptability) to skin irritation associated with cancer treatment. An additional obstacle in the path to successful transdermal delivery is the stability issue of the (bio)molecule in the drug delivery system, skin, and target tissue.