Johnson Pharmaceutical Research Research Articles

A 3-year follow-up study of atropine treatment for progressive myopia in Europeans

Learning ObjectivesUpon completion of this activity, participants will be able to:Distinguish the most salient pathological feature of high myopia.Evaluate the long-term tolerability of atropine eye drops for myopia.Analyze the long-term efficacy of atropine eye drops for myopia.Assess variables that might alter the efficacy of atropine eye drops for myopia.Continuing Medical EducationIn support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Springer Nature. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/eye; (4) view/print certificate.Credit hours1.0Release date:Expiration date: 21 September 2021Post-test link:https://medscape.org/eye/posttest934752Authors/Editors disclosure informationSobha Sivaprasad, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: Allergan, Inc.; Apellis; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Heidelberg Pharma GmbH; Novartis; Oculis; Optos; Oxurion; Roche. Served as a speaker or a member of a speakers bureau for: Allergan, Inc.; Bayer AG; Novartis Pharmaceuticals Corporation; Optos. Received grants for clinical research from: Allergan, Inc.; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos. Jan Roelof Polling, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: Théa Laboratories; Nevakar, Inc. Emily Tan, MD, has disclosed no relevant financial relationships. Sjoerd Driessen, MD, has disclosed no relevant financial relationships. Sjoukje E. Loudon, MD, has disclosed no relevant financial relationships. Hoi-Lam Wong, MD, has disclosed no relevant financial relationships. Astrid van der Schans, MD, PhD, has disclosed no relevant financial relationships. J. Willem Tideman, MD, has disclosed no relevant financial relationships. Caroline C. W. Klaver, MD, PhD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: Bayer AG; Nevakar, Inc.; Novartis Pharmaceuticals Corporation; Théa Laboratories.Journal CME author disclosure informationCharles P. Vega, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Served as a speaker or a member of a speakers bureau for: Genentech, Inc.; GlaxoSmithKline.

The current status of imaging in anti-NGF clinical trials

Purpose: Nerve Growth Factor (NGF) is a neurotrophin that regulates the structure and function of responsive sensory neurons and is a regulator of pain sensitivity and processing. The concept of targeting NGF to target chronic pain syndromes has been gaining momentum since 1990. There have been a significant number of trials conducted or being initiated. This abstract provides a review of the studies that have evaluated a-NGF compounds. Methods: A thorough review was performed on the web site www.clinicaltrials.gov to identify all a-NGF studies that have been conducted. The terms anti-NGF, and a-NGF only return a limited number of results so the individual compounds had to be identified either by their generic name or compound number. 45 studies were identified and although 2 studies had been withdrawn prior to randomization, a total of 15,664 subjects have been enrolled in studies with the aNGF mAbs. Seven of these trials have been published in peer-reviewed journals. Results: While the majority (26) of studies have been conducted by Pfizer with Tanezumab, there have been 7 with Fulranumab previously known as JNJ-42160443 (Johnson & Johnson Pharmaceutical Research & Development), and 9 with Fasinumab previously known as REGN475 (Regeneron pharmaceuticals/Sanofi). Many of the studies have been either terminated (24), or completed (16) but there is one currently active (not recruiting) in cancer-related pain (Fulranumab). There is also a study of 450 subjects with OA of the knee and hips that is planned to start recruiting in January 2014. The number of indications that have been studied comprise of osteoarthritis (21), which includes either the knee, hip or both; low back pain (4), and a variety of pain syndromes (11) including neuropathic pain from diabetes (2), plus three in cancer pain of which one is on-going. In the Tanezumab program 249 subjects were adjudicated for AEs related to the joints. Of these 68 had Rapidly Progressing Osteoarthritis (RPOA), 67 in the Phase III program and 1 in the Phase 1 program for chronic back pain. The advisory board noted that 13 of the 68 subjects had definite evidence of SIF at enrollment. This program had the largest number of enrolled subjects at the time of FDA cessation of the program (13310 subjects of the 15,664 enrolled in aNGF studies or 85%). While these subjects were identified post hoc, SIF, RPOA and joint destruction was not an AE that was anticipated a priori and therefore nothing pro-actively built into the studies to evaluate the true incidence of these events. Conclusions: In summary, medical imaging and the thorough radiological evaluation of the major articulating joints for all subjects in future aNGF studies will be required. The first step will be to rule out possible pathology or those at high risk of going onto a catastrophic joint failure. Then secondly to closely monitor the subjects during the treatment phase with radiography and if inconclusive also with magnetic resonance imaging to ensure that any possible events will be identified early and the subject managed to prevent any further bone or joint damage.

Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

IntroductionPrevious results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here.MethodsSubjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]).ResultsA total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups.ConclusionDespite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. DisclosuresOrlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS® hydromorphone ER) in patients with chronic pain

ObjectiveTo characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications.MethodsThis open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3–14 days and stabilized between 8–48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration–time curve from 0–24 hours (AUC0–24), maximum plasma concentration (Cmax), trough plasma concentration (Cmin), average plasma concentration (Cavg), and degree of fluctuation (100 × [(Cmax − Cmin) ÷ Cavg]) were calculated based on data from 14 patients.ResultsDose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC0–24, 41.1 ng · h/mL; Cmax, 2.6 ng/mL; Cmin, 1.1 ng/mL; Cavg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2–21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred.ConclusionThese findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.

Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs

Background and methodsThe role of the endogenous purine nucleoside, adenosine, in nociception is well established. Inhibition of the equilibrative nucleoside transporter (ENT1) prevents adenosine uptake into cells, and could therefore enhance the antinociceptive properties of adenosine. The effects of ENT1 inhibition were studied in two animal models of inflammatory pain. Analgesic activity was assessed in a complete Freund’s adjuvant (CFA)-induced and carrageenan-induced mechanical and thermal hyperalgesia model in the guinea pig.ResultsDraflazine, dipyridamole, dilazep, lidoflazine, soluflazine, and KF24345 showed efficacy in the CFA thermal hyperalgesia model. Draflazine, the most potent compound in this test, was further characterized in the CFA model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia, where it completely reversed the hypersensitivity. The antihyperalgesic effects of draflazine (10 mg/kg, administered subcutaneously) were attenuated by the A1 receptor antagonist, cyclopentyltheophylline (5–40 mg/kg, administered intraperitoneally), by the nonselective adenosine antagonist, caffeine (10–40 mg/kg intraperitoneally), and by the A2 antagonist, DMPX (10 mg/kg administered intraperitoneally).ConclusionENT1 inhibition is an effective way of reversing mechanical and thermal inflammatory hyperalgesia in the guinea pig, and these effects are mediated by enhancement of endogenous adenosine levels. Both A1 and A2 adenosine receptor subtypes are likely to be involved.

Trabectedin as a New Chemotherapy Option in the Treatment of Relapsed Platinum Sensitive Ovarian Cancer

Trabectedin (ET-743, Yondelis®) is a novel marine antineoplastic alkaloid with a unique mechanism of action. The active substance trabectedin, a tetrahydroisoquinoline alkaloid, is a natural product originally isolated from the Caribbean sea squirt, Ecteinascidia turbinata and is currently manufactured by total synthesis. Trabectedin is licensed by the Spanish pharmaceutical drug company, PharmaMar and co-developed by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., pursuant to a licensing agreement with PharmaMar. Trabectedin is the first anticancer marine-derived drug to be approved by the European Union. In 2007, trabectedin obtained marketing authorization from the European Commission and in many other countries worldwide for the treatment of patients with advanced soft tissue sarcoma (STS) after failure of anthracyclines and ifosfamide, or for those patients who are unsuitable to receive these agents. Based on the recently reported results of a large phase III study (OVA-301) comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer, in 2009 the European Commission granted marketing authorization for trabectedin combined with PLD for the treatment of patients with relapsed platinum-sensitive ovarian cancer. The results from OVA-301 showed that the combination of trabectedin and PLD improves progression-free survival and overall response rate over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer. In addition, an enhanced activity of trabectedin combined with PLD was observed in platinum sensitive patients, especially in those with a platinum-free interval ranging from 6 to 12 months. Overall, trabectedin-induced toxicities are mainly hematological and hepatic, with grade 3/4 neutropenia and thrombocytopenia observed in approximately 50% and 13% of patients, respectively, and grade 3/4 elevation of liver aminotransferases observed in 40-50% of patients treated with trabectedin. Current efforts are focused on the evaluation of the role of trabectedin in prolonging the platinum-free interval and the identification of predictive factors for patients treated with trabectedin as well as in the development of new trabectedin-based combinations.

Small Molecule Compound Logistics Outsourcing – Going Beyond the “Thought Experiment”

Increasing pressure on the pharmaceutical industry to reduce cost and focus internal resources on "high value" activities is driving a trend to outsource traditionally "in-house" drug discovery activities. Compound collections are typically viewed as drug discovery's "crown jewels"; however, in late 2007, Johnson & Johnson Pharmaceutical Research & Development (J PRD) took a bold step to move their entire North American compound inventory and processing capability to an external third party vendor. The authors discuss the combination model implemented, that of local compound logistics site support with an outsourced centralized processing center. Some of the lessons learned over the past five years were predictable while others were unexpected. The substantial cost savings, improved local service response and flexible platform to adjust to changing business needs resulted. Continued sustainable success relies heavily upon maintaining internal headcount dedicated to vendor management, an open collaboration approach and a solid information technology infrastructure with complete transparency and visibility.

Vitamin B12 and Neurological Function: Is There a Threshold Level? (P02.059)

Objective: To evaluate a threshold serum vitamin B12 level on central and peripheral neurological function. Background Low vitamin B12 levels ( Design/Methods: Participants were from the Health ABC Study, a prospective cohort of well-functioning adults aged 70-79 years in 1997-98. We included 2326 participants (mean age: 76.5±2.9 years; 48.6% male, 38.4% black; 21.6% diabetes) with 2000-01 serum B12 levels and ≥1 neurological measure: 1.4g/10g monofilament detection; average vibration threshold; peroneal nerve conduction amplitude [CMAP] and velocity [NCV] (all 2000-01); Digit Symbol Substitution Test [DSST] scores (2001-02). Of these, 1226 participants (mean age: 76.1±2.8 years; 47.1% male, 34.2% black; 18.9% diabetes) had ≥1 follow-up neurological measure in 2007-08 for the longitudinal analyses. Results: Adjusting for demographics, body composition, socioeconomic/lifestyle factors, CES-D score, medications, and chronic health conditions, we found significant vitamin B12 threshold levels of 390 pmol/L for higher NCV (p=.02) and of 410 pmol/L for lower DSST decline (p=.01). A threshold level of 400 pmol/L for 1.4g monofilament detection was significant unadjusted (p=.04), but this and other outcomes were not significant after adjustment. Conclusions: Higher B12 levels (∼400 pmol/L), 2.7 times higher than the current clinical cutpoint for deficiency, may be necessary for optimal neurological function and lower decline in older adults. These results are important since poor peripheral nerve function and slower processing speed may lead to impaired physical and cognitive function and disability. Future studies of vitamin B12 in older adults should rigorously evaluate neurological outcomes. Supported by: The National Institutes on Aging (NIA) contract numbers N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; and in part by the NIA Intramural Research Program of the NIH; NIA grant R01-AG 028050 (Strotmeyer ES); and NINR grant R01-NR012459; University of Pittsburgh Claude D. Pepper Older Americans Independence Center (P30-AG024827) Pilot Grant (Strotmeyer ES), and the NIA training grant (T32-AG-000181 KL). Disclosure: Dr. Leishear has nothing to disclose. Dr. Boudreau has nothing to disclose. Dr. Studenski has nothing to disclose. Dr. Ferrucci has nothing to disclose. Dr. Rosano has nothing to disclose. Dr. de Rekeneire has nothing to disclose. Dr. Houston has nothing to disclose. Dr. Kritchevsky has nothing to disclose. Dr. Schwartz has nothing to disclose. Dr. Vinik has received personal compensation for activities with Ansar, Eli Lilly & Company, KV Pharmaceuticals, Merck & Co., Inc., Novartis, R.W. Johnson Pharmaceutical Research Institute, Sanofi-Aventis Pharmaceuticals, Inc., and Takeda Pharmaceuticals. Dr. Vinik has received research support from Abbott Laboratories, Inc., GlaxoSmithKline, Inc., Sanofi-Aventis Pharmaceuticals, Inc., Arcion Therapeutics, Reliant Pharmaceuticals, Eli Lilly & Company, and Merck Research Labs. Dr. Hogervorst has nothing to disclose. Dr. Yaffe has received personal compensation for activities with Pfizer Inc, Novartis, and Medivation. Dr. Harris has nothing to disclose. Dr. Newman has nothing to disclose. Dr. Strotmeyer has nothing to disclose.

Enhanced Bioavailability of a Poorly Water-Soluble Weakly Basic Compound Using a Combination Approach of Solubilization Agents and Precipitation Inhibitors: A Case Study

Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 μg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 μg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.

Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF

In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0-3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77-1·16) and those without (1·44%vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69%vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08). There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF. Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

Biologics and molecular recognition: Mike Brigham‐Burke memorial issue

Biologics and molecular recognition: Mike Brigham‐Burke memorial issue

A Novel Use of Dignity Therapy

Back to table of contents Previous article Next article Communications and UpdatesFull AccessA Novel Use of Dignity TherapyJonathan D. Avery, M.D., and Adam J. Savitz, M.D., Ph.D.Jonathan D. AveryNew YorkSearch for more papers by this author, M.D., and Adam J. SavitzNew YorkSearch for more papers by this author, M.D., Ph.D.Published Online:1 Dec 2011https://doi.org/10.1176/appi.ajp.2011.11030444AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dignity therapy is a brief psychotherapeutic intervention for terminally ill patients (1). In this therapy, patients generate a document to pass on to loved ones that contains details of the patient's life, life lessons, and declarations of affection. Clinicians help create such documents by recording the patient's story over several interviews and then transcribing and editing the patient's words. We report the case of a 55-year-old man with severe mental illness who participated in dignity therapy while awaiting transfer to a state hospital.Case Report“Mr. J” is a 55-year-old man with schizoaffective disorder and multiple psychiatric hospitalizations who was admitted for worsening paranoia and agitation. Despite stabilization with medications, he continued to require hospitalization because of his poor self-care, and he was referred to the state hospital.While awaiting transfer, Mr. J worried that he would never spend meaningful time with his adult children, and he agreed to undergo dignity therapy to tell his life story to his children. He was too paranoid to participate in a recorded interview, but he agreed to write his story following the prompts in the dignity psychotherapy protocol (1), which contains questions about life history, dreams, and accomplishments. He wrote his own answers in a simple, grammatically incorrect style, but one of the authors (J.D.A.) typed up his words, edited them, and reviewed them with him. Mr. J focused primarily on the births of his children and the course of his illness, and he concluded by expressing his love toward his children. He distributed 10 copies of his story to family and friends. He reported that dignity therapy had “restored hope” and enabled him to communicate better with his children, who stated that they could now better understand their father.DiscussionIn this case, dignity therapy helped a patient with a debilitating mental illness face a negative life event much in the way it helps those facing terminal illness. In palliative care, dignity therapy has helped patients achieve a greater sense of purpose and will to live and reduced their suffering and depressive symptoms (1). Such gains would be beneficial for individuals with chronic mental illnesses, who have often suffered many personal losses and have low quality-of-life scores (2). Dignity therapy, along with other forms of psychotherapy (3), has the potential to improve patients' personal narratives, and future research to adapt dignity therapy for people with mental illness may increase patients' self-worth and coping abilities.New YorkDr. Avery reports no financial relationships with commercial interests. Dr. Savitz is employed full-time by Johnson & Johnson Pharmaceutical Research and Development and has received research support from Abbott Laboratories and Sanofi-Aventis.Accepted for publication in June 2010.

A Phase 2 Multicenter Study of Siltuximab, An Anti-IL-6 Monoclonal Antibody, in Patients with Relapsed or Refractory Multiple Myeloma,

A Phase 2 Multicenter Study of Siltuximab, An Anti-IL-6 Monoclonal Antibody, in Patients with Relapsed or Refractory Multiple Myeloma,

Efficient Substructure Searching of Large Chemical Libraries: The ABCD Chemical Cartridge

Efficient substructure searching is a key requirement for any chemical information management system. In this paper, we describe the substructure search capabilities of ABCD, an integrated drug discovery informatics platform developed at Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The solution consists of several algorithmic components: 1) a pattern mapping algorithm for solving the subgraph isomorphism problem, 2) an indexing scheme that enables very fast substructure searches on large structure files, 3) the incorporation of that indexing scheme into an Oracle cartridge to enable querying large relational databases through SQL, and 4) a cost estimation scheme that allows the Oracle cost-based optimizer to generate a good execution plan when a substructure search is combined with additional constraints in a single SQL query. The algorithm was tested on a public database comprising nearly 1 million molecules using 4,629 substructure queries, the vast majority of which were submitted by discovery scientists over the last 2.5 years of user acceptance testing of ABCD. 80.7% of these queries were completed in less than a second and 96.8% in less than ten seconds on a single CPU, while on eight processing cores these numbers increased to 93.2% and 99.7%, respectively. The slower queries involved extremely generic patterns that returned the entire database as screening hits and required extensive atom-by-atom verification.

Plasma IL-22 Levels, But Not IL-17, are Significantly Higher in Inflammatory Bowel Disease Patients Compared to the Healthy Adults

Purpose: Inflammatory Bowel Disease (IBD) is characterized by abnormal and exacerbated immune response in gastrointestinal (GI) tract. The recent discovery of T helper 17 cells (Th17) and its signature cytokines, Interleukin-17 (IL-17) and Interleukin-22 (IL-22), represent an important mechanism in immune regulation. Our study objective is to compare plasma IL-17 and IL-22 levels in IBD patients and healthy controls. Methods: In our ongoing prospective cohort study, we have enrolled 17 patients with either Ulcerative Colitis (UC) (n=7) or Crohn's Disease (CD) (n=10) and 18 healthy controls. We measured the serum levels of IL-17 and IL-22 in all the IBD patients and healthy controls using ELISA assays according to the manufacturer's instructions. Results: Comparisons were made in the serum levels of IL-22 and IL-17 between healthy controls and IBD patients as well as between healthy controls and UC and CD separately. Wilcoxon 2 sample test was used to test the equality of medians between groups. Plasma IL-22 levels were significantly higher in IBD group when compared with controls (p-value of 0.004). Similarly, plasma IL-22 levels were significantly higher in both UC and CD when compared separately with healthy controls (p-value of 0.007 and 0.01, respectively). Plasma IL-17 did not show any significant difference between IBD and healthy controls as well as UC and CD with healthy controls (p-value of 0.76, 0.74 and 0.87, respectively). Conclusion: IL-22 is a strong activator of the pro-inflammatory gene expression in IBD. The exact function of IL-22 in human IBD still remains to be elucidated. The levels of plasma IL-22 were significantly higher in both UC and CD when compared to the healthy controls. Therefore, we believe that better understanding of the role of IL-22 might provide a valuable insight into the pathogenesis of IBD. This research was supported by an industry grant from Johnson and Johnson Pharmaceutical Research and Development, L.L.C.

Prediction of Human Oral Plasma Concentration-Time Profiles Using Preclinical Data

Empirically based methods remain one of our tools in human pharmacokinetic predictions. The Dedrick approach and the steady-state plasma drug concentration (C(ss))-mean residence time (MRT) approach are based on the assumption that concentration-time profiles are similar among species, including man, and that curves derived from a variety of animal species can be superimposed after mathematical transformation. In the Dedrick approach the transformation is based on the slope and intercept of the allometric relationship. The C(ss)-MRT approach is based on the implementation of measured animal and predicted human MRT and dose/volume of distribution at steady state (V(ss)). The aims of the present study were to compare the predictive performance of concentration-time profiles obtained by these approaches, to evaluate the prediction of individual pharmacokinetic parameters by these approaches and to further refine these approaches incorporating the experience from our previous work. A retrospective analysis using 35 proprietary compounds developed at Johnson & Johnson Pharmaceutical Research and Development was conducted to compare the accuracies of the Dedrick and C(ss)-MRT approaches for predicting oral concentration-time profiles and pharmacokinetic parameters in man. In the first step, input for the transformation was based on simple allometry. Then we assessed whether both methods could be fine-tuned by systematically incorporating correction factors (maximum life span potential, brain weight and plasma protein binding), depending on the interspecies relationship. In addition, for the C(ss)-MRT approach, we used formulas based on multivariate regression analysis as input for the transformation. Inclusion of correction factors significantly improved the profile predictability for the Dedrick and C(ss)-MRT approaches. This was mainly linked to an improved prediction of terminal elimination half-life (t(½)), MRT and the ratio between the maximum plasma concentration and the concentration at the last observed time point (C(max)/C(last)). No significant differences were observed between the Dedrick approach with correction factors, the C(ss)-MRT approach with correction factors and the C(ss)-MRT approach, based on the regression equations. Based on the dataset evaluated in this study, we demonstrated that human plasma concentration-time profiles and pharmacokinetic parameters could be predicted with the Dedrick and C(ss)-MRT approaches and that if correction factors were implemented, the predictions improved significantly. With the requirement of only a limited preclinical in vivo pharmacokinetic dataset, these empirical methods could offer potential in the early stages of drug discovery.

Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial

Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.

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Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study

Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma. This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m(2), on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.

Impact of pain relief with fulranumab in the treatment of patients with moderate to severe osteoarthritis pain

Chronic pain impacts many aspects of patients’ lives, including their ability to perform daily activities and obtain adequate sleep. Fulranumab, a human recombinantmonoclonal antibody to human nerve growth factor, is being investigated for chronic pain treatment. Impact of pain relief on patient-reported functioning, activities and sleep was evaluated during the 12-week efficacy phase of an ongoing 104-week, phase 2, double-blind, placebo-controlled trial designed to assess fulranumab’s analgesic efficacy and tolerability, in addition to current pain therapy, in patients with inadequately controlledmoderate-tosevere osteoarthritis pain (hip and knee). Randomized patients received subcutaneous injections in one of six groups: placebo, fulranumab 1mg or 3mg every 4 weeks (Q4wk), or fulranumab 3mg, 6mg, or 10mg every 8 weeks (Q8wk). The SF-36, Brief Pain Inventory-Short Form (BPI), and MOS Sleep Scale (MOS-SS) were completed at baseline and endpoint (12 weeks). Patients also answered a daily question on pain interference with sleep. Primary efficacy and detailed safety results are presented elsewhere. Patients (N=466, intent-to-treat) were 58%women, 85%white, age 61 years. Most SF-36 subscales, including physical functioning, improved: significant improvements versus placebo occurred for Bodily Pain subscale (3mgQ4wk and 10mgQ8wk groups; p<0.04), Vitality Subscale (3mgQ4wk, 3mgQ8wk, 6mgQ8wk and 10mgQ8wk groups; p<0.04), and Physical Component Subscale (10mgQ8wk group; p=0.01). Fulranumab, significantly (p<0.03 versus placebo) improved the BPI Pain Intensity Subscales and Pain Interference with Activities subscale scores (3mgQ4wk and 10mgQ8wk groups). Fulranumab 3mgQ4wk, 3mgQ8wk, and 10mgQ8wk also significantly (p<0.05 versus placebo) improvedpain interferencewith sleep. SleepAdequacy (MOS-SS) improved across fulranumab groups (p<0.03 versus placebo). Fulranumab, in addition to improving pain, improved functioning, vitality and the degree to which pain interfered with activities of daily living and sleep, areas often impacted in patients with moderate-to-severe osteoarthritis pain. Funded by Johnson & Johnson Pharmaceutical Research & Development, LLC.