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Thursday, December 27, 2018

Abuse of Xanax, Valium on Rise


About one in every five people who take Valium, Xanax and other benzodiazepines are misusing the potentially addictive medication, U.S. survey data show.
The statistics also revealed that benzodiazepine use among adults is more than twice as high as previously reported, with nearly 13 percent using the drugs within the past year.
Studies from 2013 and 2014 estimated that between 4 percent and 6 percent of adults were taking benzodiazepines, which also include Halcion and Klonopin.
Young adults aged 18 to 25 are most likely to misuse benzos, which are typically prescribed to treat conditions like anxiety and depression, said lead researcher Dr. Donovan Maust. He’s an assistant professor with the University of Michigan’s department of psychiatry.
“If you look at younger adults, basically misuse was as common as prescribed use, which obviously is kind of disturbing,” Maust said.
These results jibe with reports earlier in the year warning that overdose deaths related to benzos have increased exponentially over the past decade, in lockstep with a steady growth in prescription rates.
Benzo-related overdoses multiplied sevenfold between 1999 and 2015, increasing from 1,135 to 8,791 deaths, according to a February report in the New England Journal of Medicine.
There’s also a link to America’s ongoing opioid crisis. Nearly one in three overdoses caused by opioids also involve benzos, according to the U.S. National Institute on Drug Abuse.
Linda Richter is director of policy research and analysis with the Center on Addiction. She said, “The risk of poisoning from benzodiazepines alone is very high, but is compounded for those who misuse benzodiazepines — a central nervous system depressant — along with opioids, which suppress respiration. When combined with alcohol, also a depressant, the effects can be similarly severe.”
For this study, Maust and his colleagues reviewed results from the 2015 and 2016 National Survey on Drug Use and Health, an annual nationwide survey funded by the U.S. Substance Abuse and Mental Health Services Administration.
Older adults are most commonly prescribed benzodiazepines. But, Maust said, “We knew almost nothing about how common misuse was among older adults, which is a big gap in our knowledge.”
Misuse means using benzos in any way a doctor did not direct, including using the drugs without a prescription, taking higher doses than prescribed, or taking them more often or longer than prescribed.
Overall, about 25.3 million adults said they used benzodiazepines as prescribed during the previous year, and another 5.3 million said they’d misused the drugs, the findings showed.
Researchers were surprised to learn that middle-aged folks aged 50 to 64 now are taking benzos more often than any other age group, with a little more than 14 percent reporting any past-year use.
Previous studies had found the most benzodiazepine use among seniors 65 and older, but this survey reported 13 percent taking the drugs in that age group.
Misuse was most common among young adults aged 18 to 25, with 5.2 percent reporting they’d misused benzos within the past year — more than the 5 percent in that age group who reported using the drugs as prescribed.
Richter explained that “there is a general misperception among young people that prescribed medications are inherently safer than illicit drugs, which we know is not always true and which the current prescription opioid epidemic has demonstrated to be a potentially lethal misconception.”
She added that “many young people turn to these medications to self-treat symptoms of stress or anxiety, in part because clinical therapies and treatments are too costly or inaccessible, are seen as too time-consuming, or carry too much stigma.”
In addition, Richter pointed out that “many young adults are underinsured; do not have a primary care physician; feel overwhelmed and stressed by work, school and family or social obligations; and have grown up in an age in which a ‘pill for every ill’ is the norm.”
Misuse of benzodiazepines declined with age, the investigators found: 3.3 percent among those aged 26 to 34; 1.7 percent among those aged 35 to 49; 1.4 percent among people aged 50 to 64; and just 0.6 percent among people 65 and older.
Most of the safety concerns revolving around benzo use had been focused on older adults, Maust said. For example, the sedating drugs increase the risk of falls and fractures, as well as car accidents and memory loss.
These results show that overdose risk should be considered just as strongly, particularly among younger age groups, he noted.
“If I were a clinician, the top of my list for who I would want to address benzo use in would be people who are also prescribed an opioid,” Maust said. “Next on the list would be people who drink alcohol, because again the concern with benzos is around other substances or medications that are sedating, and the bad effects when you have multiple things on board that are sedating.”
Benzodiazepines are being prescribed far too frequently, given that evidence reviews have shown that benzos are of little to no value in treating anxiety, panic disorders or insomnia, Maust said.
Cognitive behavioral therapy and psychotherapy often outperform benzodiazepines, and the drugs have been shown to actually interfere with the effects of such proven treatments, he added.
“Benzos for anxiety is like opioids for chronic pain. There’s a small subset of patients with treatment-resistant conditions where use may be appropriate,” Maust said. “The current amount of use way, way exceeds what the evidence would support.”
The new study was published online recently in the journal Psychiatric Services.
More information
The U.S. National Institute on Drug Abuse has more about benzodiazepines.
SOURCES: Donovan Maust, M.D., assistant professor, department of psychiatry, University of Michigan, Ann Arbor; Linda Richter, Ph.D., director, policy research and analysis, Center on Addiction; Dec. 17, 2018, Psychiatric Services, online

PTSD Drug May Do More Harm Than Good


A drug used to treat post-traumatic stress disorder (PTSD) may actually be harmful, a new study suggests.
The high blood pressure drug prazosin is sometimes used to treat PTSD-related nightmares and insomnia that can increase suicide risk. But this small study suggests the drug may make nightmares and insomnia worse and not reduce suicidal thoughts in PTSD patients.
“I think we have to view this as not the final word on this, but it raises questions,” said study author Dr. W. Vaughn McCall. He’s chairman of psychiatry and health behavior at the Medical College of Georgia.
The study included 20 PTSD patients, including two military veterans and several civilian women who had been sexually assaulted. All had active suicidal thoughts, some had previously attempted suicide, and most were taking antidepressants and/or had them prescribed for the study.
For eight weeks, participants took prazosin at bedtime with an aim of preventing nightmares and suicidal thoughts. They were assessed weekly for severity of suicidal thoughts, nightmares, insomnia, depression and PTSD.
The drug “did not seem to do much for suicidal ideation and that was somewhat disappointing, but the thing what was mind-blowing was that it actually worsened nightmares,” McCall said in a university news release. “Maybe it’s not for everybody.”
The unexpected increase in nightmares and insomnia might owe to the severity of a patient’s PTSD or the once-a-day dose of prazosin, he said.
PTSD patients’ nightmares often focus on the trauma that caused their PTSD, he said.
Two patients required emergency inpatient psychiatric care, but there were no suicide attempts or deaths during the study, which was published recently in the Journal of Clinical Psychopharmacology.
Prazosin may help some PSTD patients, but may not be a good choice when suicide is an active concern, according to McCall, who is now seeking input from PTSD experts across the United States
Two larger studies in active and retired military personnel yielded mixed results as well, he noted.
“We need to reconcile how is it that we had 10 years of data saying prazosin is good for nightmares in PTSD, a big study this February indicating it has essentially no [effect] and now a smaller study showing it can worsen some aspects,” McCall said. “We need to know what it all means.”
The antidepressants sertraline (Zoloft) and paroxetine (Paxil) are the only U.S. Food and Drug Administration-approved PTSD drug therapies, he said, adding that neither is widely effective.
More information
The U.S. National Institute of Mental Health has more on PTSD.
SOURCE: Medical College of Georgia, news release, November 2018

ANI Refinances Convertible Debt Due Dec 2019, Amends 5-Yr $265M Senior Credit


ANI Pharmaceuticals, Inc. (“ANI” or the “Company”) (Nasdaq: ANIP) today announced that it has entered an amended and restated five-year Senior Secured Credit Facility (the “Facility”) for up to $265.2 millionwith its existing syndicate of bank lenders (the “Bank Group”). The Facility amends ANI’s current $125 million Senior Secured Credit Facility and is structured to provide ANI flexibility in refinancing its 3.00% Convertible Senior Notes due 2019 (“the Convertible Notes”). The principal feature of the Facility is a new $118.0 million Delayed Draw Term Loan available to refinance ANI’s Convertible Notes maturing in December 2019. The Delayed Draw Term Loan is fully committed by the Bank Group and can be accessed by ANI at any time and in multiple tranches through December 1, 2019, subject to satisfaction of certain conditions precedent. The second feature is the extension of $72.2 million of Term Loan-A debt currently outstanding under the existing facility. In addition, the Facility increases the existing $50.0 million Senior Secured Revolving Credit Facility to $75.0 million. Both the Delayed Draw Term Loan and Senior Secured Revolving Credit Facility are undrawn as of this time.  Interest on the Facility is LIBOR based and generally consistent with ANI’s current borrowing arrangements with the Bank Group. The Facility is secured by the assets and equity interests of ANI and guaranteed by certain of its subsidiaries.
The Lead Arranger and Administrative Agent for the Facility is Citizens Bank, N.A. The Bank of Tokyo-Mitsubishi UFJ, Ltd. and The Huntington National Bank acted as Joint Lead Arrangers, while Regions Bank acted as Documentation Agent. The Facility is also funded by U.S. Bank National Association and J.P. Morgan Chase Bank, N.A.

Immunotherapy Company Harpoon Therapeutics Discloses IPO Plans


Harpoon Therapeutics Inc., an immunotherapy company developing T cell engagers intended to treat cancer and other diseases, on Thursday disclosed plans for an initial public offering.
The South San Francisco, Calif., company previously filed confidential IPO paperwork.
Harpoon closed a $70 million Series C equity financing round in November. Its largest shareholders included MPM Capital, which has 23.3% stake, and UBS Oncology Impact Fund, with 20.2%.
Harpoon and AbbVie Inc. (ABBV) entered an immuno-oncology research collaboration in 2017. The agreement calls for Harpoon to engineer TriTAC molecules directed against selected cancer targets.
According to Harpoon’s Form S-1 filing, the agreement included a $17 million up-front payment.
Harpoon’s lead TriTAC product candidate, HPN424, is currently in a Phase 1 clinical trial for the treatment of metastatic castration-resistant prostate cancer.
The filing lists an amount of $86.25 million but this is a placeholder figure used to calculate registration fees. Harpoon has applied to list on the Nasdaq Global Select Market under the symbol HARP.

New BP treatment cutoffs may not yield survival benefit


New blood pressure treatment recommendations may not improve survival from cardiovascular disease (CVD), according to a study recently published in the European Heart Journal.
Seryan Atasoy, from the Ludwig-Maximilians-Universitüt München, and colleagues used data from 11,603 participants (52 percent men; mean age, 47.6 years) in the MONICA/KORA prospective study. The authors sought to evaluate the prevalence of hypertension and associated CVD events.
They found that implementation of the new Stage 1 cutoff (130 to 139 mm Hg systolic or 80 to 89 mm Hg diastolic) increased the prevalence of hypertension from 34 to 63 percent. Only 24 percent of Stage 2 hypertension patients (≥140/90 mm Hg) were receiving treatment. During 10 years of follow-up, there were 370 fatal CVD events. The adjusted CVD-specific mortality rate per 1,000 persons was 1.61 (95 percent confidence interval, 1.10 to 2.25) and 1.07 (percent confidence interval, 0.71 to 1.64) in Stage 2 hypertension and Stage 1 hypertension cases, respectively, compared with those with normal blood pressure. The association of Stage 2 hypertension and CVD mortality was significant in Cox proportional regression models (1.54; 95 percent confidence interval, 1.04 to 2.28; P = 0.03), while the association was not significant for Stage 1 hypertension (0.93; 95 percent  interval, 0.61 to 1.44; P = 0.76).
“The lower BP cutoff substantially increased  prevalence, while capturing a population with lower CVD mortality,” the authors write.

Bio-Path Holdings (BPTH) Clinical Update, 2019 Business Outlook


Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize® antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, today provides an update from several clinical development programs and a 2019 business overview.
“Over the last year, we made solid progress across our growing development pipeline, highlighted by positive interim data from our Phase 2 study of prexigebersen in de novo acute myeloid leukemia (AML) patients,” stated Peter H. Nielsen, chief executive officer of Bio-Path Holdings. “We enter 2019 focused and optimistic about our prospects for the clinical advancement of our pipeline of RNAi nanoparticle drugs in patients suffering from a variety of cancers of unmet medical need.”
Phase 2 Study of Prexigebersen in De Novo AML Patients
In August 2018, Bio-Path announced first patient dosed in Stage 2 of the open-label Phase 2 study evaluating the efficacy and safety of prexigebersen (an antisense RNAi nanoparticle against Grb2 protein) in combination with LDAC and a second cohort of prexigebersen and decitabine, both therapeutic regimens well established in treatment of acute myeloid leukemia (AML) patients who cannot or elect not to be treated with more intensive chemotherapy. The primary objective of the study is to determine whether these combinations with prexigebersen provide greater efficacy than what would be expected with low-dose cytarabine (LDAC) or decitabine alone in this de novo patient population. In 2019, Bio-Path expects to open three trial sites in the EU, which Bio-Path expects will accelerate patient enrollment.
As previously announced, a planned interim analysis of Stage 1 of the study was performed on 17 evaluable patients, with four patients achieving complete responses (24%) and four patients achieving stable disease, including one patient achieving a morphologic leukemia free state and one patient who showed significantly reduced bone marrow blasts. In total, 47% of the evaluable patients showed some form of response, including stable disease, to the prexigebersen and LDAC combination treatment.
Efficacy data are encouraging in this challenging population in which the majority of patients had secondary AML or adverse-risk AML, and compares favorably to the reported CR (complete remission), CRp (complete remission with incomplete platelet recovery), and CRi (complete remission with incomplete hematologic recovery) rate with LDAC alone of 7-13%1.
Plans for a pivotal trial are expected to be discussed with the FDA if these results exceed expectations for current standard-of-care therapy.
Phase 2a Study of Prexigebersen in Accelerated and Blast Phase CML Patients
Bio-Path plans to continue enrolling patients in 2019 in a Phase 2a clinical study of prexigebersen in combination with the frontline therapy, dasatinib, for the treatment of chronic myeloid leukemia (CML) in accelerated and blast phase patients. For 2019, additional sites are planned to be added and enrollment planned to be opened across both phases of the disease, including imatinib-resistant chronic phase patients. The trial is currently being conducted at The University of Texas MD Anderson Cancer Center as a potential salvage therapy for accelerated and blast phase CML patients.
Two cohorts of three evaluable patients each are expected to be enrolled to evaluate two doses (60 mg/m2 and 90 mg/m2) of prexigebersen in combination with dasatinib.
Phase 1 Study of Prexigebersen in Patients with Advanced Solid Tumors
In 2019, Bio-Path intends to initiate a Phase 1 clinical trial of prexigebersen in patients with advanced solid tumors, including ovarian and uterine, pancreatic and hormone refractory breast cancer. This trial is expected to be conducted at several leading cancer centers and is planned to evaluate the safety of prexigebersen in combination with standard-of-care for each tumor type.
Phase 1 Study of BP1002 in Refractory or Relapsed Lymphoma Patients
Bio-Path expects to initiate a Phase 1 clinical trial of BP1002, an antisense RNAi nanoparticle targeting the Bcl-2 protein, in refractory or relapsed lymphoma and chronic lymphocytic leukemia (CLL) patients in 2019. The clinical trial is expected to be conducted at several premier cancer centers and is planned to evaluate the safety of BP1002 in several dose escalating cohorts to determine a maximum tolerated dose.
Preclinical Development of BP1003
The Company continues to advance its third investigation drug candidate, BP1003, for the treatment of advanced solid tumors, including pancreatic cancer. BP1003 is an antisense RNAi nanoparticle targeting the Stat3 protein. Bio-Path intends to initiate several Investigational New Drug application (IND) enabling studies for BP1003 in 2019.

Cancer Treatment and Arthritis: A Growing Complaint


Rheumatic adverse events such as inflammatory arthritis continue to accrue with the burgeoning use of immune checkpoint inhibitors (ICIs) in the treatment of cancer, presenting challenges in management for both rheumatology and oncology.
At the annual meeting of the Florida Society of Rheumatology in July, Andrew Ostor, MD, of Cabrini Medical Center in Melbourne, Australia, predicted an ever-increasing number of these complications.
“It’s likely that the rheumatic complications of these drugs will become more common than rheumatoid arthritis itself,” he stated.
The ICIs block co-stimulatory molecules on T-cells, antigen presenting cells, and tumor cells, which results in unchecked T-cell activation and the upregulation of tumor targeting by the immune system — the opposite of the immunosuppression that is the goal of much treatment for conditions such as rheumatoid arthritis and lupus.
The agents currently available include ipilimumab (Yervoy), which targets cytotoxic lymphocyte antigen 4 (CTLA-4); nivolumab (Opdivo) and pembrolizumab (Keytruda), which target programmed cell death protein 1 (PD-1); and atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio), which target programmed death ligand 1 (PD-L1). Numerous other ICIs are currently being developed.
The growing number of immune-related adverse events associated with ICIs have included colitis, rash, pancreatitis, and pneumonitis, and rheumatic conditions such as arthritis, myositis, vasculitis, sicca syndrome, and polymyalgia rheumatica. Guidelines have been established for managing colitis and pneumonitis, but only preliminary recommendations are available for the management of the rheumatic events.
The Mayo Cohort
A recent publication in Arthritis & Rheumatology from the Mayo Clinic in Rochester, Minnesota, reported on 61 cases of rheumatic syndromes in patients being treated with ICIs from 2011 to 2018. When asked if the incidence of these complications will likely continue to rise, lead author Uma Thanarajasingam, MD, told MedPage Today, “We don’t have a definite answer to this as yet, but I would expect that as the number of checkpoint inhibitors approved for clinical use expands, as well as the clinical indications for their use, we will be seeing a greater number of rheumatic toxicities.”
The most common event in this series was inflammatory arthritis, which developed in 34 patients, whose mean age was 59. The condition was polyarticular in two-thirds. The inflammatory arthritis was most common among patients treated with combination anti-CTLA-4/PD-1 treatment (4%), compared with 2% of those who were given anti-PD-1 or anti-PD-L1 (2%) or anti-CTLA-4 monotherapy (1%).
The treatment was prednisone alone in 62% of patients, with a mean starting dose of 30.6 mg/day and mean time on steroids being 18 weeks. An additional 15% received a disease-modifying antirheumatic drug along with the steroid, and 24% also were given nonsteroidal anti-inflammatory drugs or intra-articular steroids. The arthritis resolved completely in 47% and partially in 53%.
10 of the patients in the Mayo cohort developed myopathy, which was the most severe type of rheumatic adverse event. Treatment for these patients consisted of prednisone alone in half of the patients, with mean starting doses of 74 mg/day. The remainder required intravenous methylprednisolone, and complete resolution was seen in 70%. Two patients died from complications associated with myocarditis and bulbar myopathy.
Treatment for these patients currently is based on expert opinion, according to Thanarajasingam. “Prospective trial-based data for the treatment of rheumatic toxicities are lacking at present, and will likely require multicenter collaboration and study, which I hope will be achieved in the near future,” she said.
The Hopkins Cohort
Another recent series included 30 patients from Johns Hopkins University in Baltimore reported in Seminars in Arthritis & Rheumatism.
The patients, whose median age was 59, had been seen from 2013 to 2017. A total of 40% were women. The most common types of tumor were non-small cell lung cancer, in 40%, and melanoma, in 23.3%. All had been treated with monotherapy with an anti-PD1 or anti-PD-L1 agent (n=16) or combination therapy with an anti-PD-1 plus a CTLA-4 agent (n=14). 10 had experienced a complete tumor response.
More than half of patients presented with involvement of one or both knees, which was particularly common in the combination therapy group, whereas patients receiving monotherapy more often had initial symptoms in the small joints of the hands. Time to onset of arthritis varied from 1 to 24 months (mean 6.2 months), suggesting a significant delay in diagnosis, particularly for those with small joint involvement, the researchers said.
Two-thirds of patients had additional immune-related adverse events — most commonly colitis but also pneumonitis and skin rash. Patients receiving combination therapy more often had colitis, suggesting involvement of the Th17 pathway.
Systemic corticosteroids were used for 24 patients, and 10 required additional immunosuppression, particularly those who had been given combination therapy. Seven patients were treated with tumor necrosis factor (TNF) inhibitors, and all showed improvement of their arthritis. Four of the TNF inhibitor recipients had complete tumor responses at the time of arthritis treatment initiation.
This study was the first to assess the clinical pattern of arthritis according to cancer treatment regimen, noted the researchers, led by Laura Cappelli, MD.
“This is critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced inflammatory arthritis and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced inflammatory arthritis and subsequently refer patients to rheumatology,” the team wrote.
Outcomes and Impact
Some of these toxicities resolve with stopping the checkpoint inhibitor and administering steroids or other treatments, but others have persisted long after the cancer treatment is withdrawn. “These are particularly challenging cases to manage, and it is my suspicion that at least a subset of cases are actually an unmasked pre-existing tendency to autoimmunity,” Thanarajasingam said.
“For many patients, the symptoms eventually resolve with the cessation of the immune checkpoint inhibitor,” Cappelli told MedPage Today. “But there is a subset of patients who go on to have chronic inflammatory arthritis. We’re working to study this question in depth and to see how many patients develop this. Our best guess now is probably 20% to 25%.”
As to the potential impact of treatment of the adverse events on cancer treatment, “the jury is still out,” Thanarajasingam noted. In the Hopkins cohort, none of the patients who received anti-TNF treatment for their arthritis have thus far experienced a loss of cancer response.
“But there are conflicting reports in the literature as to the impact of steroids (the current mainstay of therapy) on overall survival and progression-free survival,” Thanarajasingam said. Some retrospective studies have found no impact, whereas others found a slight negative influence on survival. “We need more prospective longitudinal data from large patient cohorts to better answer this critical question,” she said.
And as to whether there might be a potential adverse impact of the arthritis treatment on cancer, that is an active area of research, Cappelli explained in an interview.
“It turns out that it might be the opposite. If you look at melanoma and lung cancer, people who developed some kind of immune-related adverse event actually had better responses to certain immune checkpoint inhibitors than those who didn’t develop immune-related adverse events,” she said. “So those issues may actually be a marker of who’s going to respond well in terms of their cancer therapy.”