Acceptable Adverse Effect Profile Research Articles

Low-Dose TMP-SMX for Pneumocystis jirovecii Pneumonia Prophylaxis in Pediatric Solid Organ Transplant Recipients.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that adversely affects solid organ transplant (SOT) recipients. Published guidelines endorse 5 to 10 mg/kg/day (trimethoprim component) trimethoprim-sulfamethoxazole (TMP-SMX) as the recommended regimen for PJP prevention, often resulting in drug-related adverse effects. We investigated the use of a low-dose TMP-SMX regimen given at 2.5 mg/kg/dose once daily every Monday, Wednesday, and Friday at a large pediatric transplantation center. A retrospective chart review was conducted, including patients ages 0 to 21 years who underwent SOT from January 1, 2012, to May 1, 2020, and who were subsequently started on PJP prophylaxis with low-dose TMP-SMX for a minimum of 6 months. The primary end point was the incidence of breakthrough PJP infection on the low-dose TMP-SMX regimen. Secondary end points include the prevalence of adverse effects characteristic of TMP-SMX. A total of 234 patients were included in this study, and 6 of 234 patients (2.6%) were empirically transitioned to treatment dosing of TMP-SMX given a clinical concern for PJP, although none received a diagnosis of PJP. There were 7 patients (2.6%) who experienced hyperkalemia, 36 (13.3%) had neutropenia, and 22 (8.1%) had thrombocytopenia (all grade 4). Clinically significant serum creatinine elevations were seen in 43 of 271 patients (15.9%). Elevations of liver enzymes were seen in 16 of 271 patients (5.9%). Rash was documented in 4 of 271 patients (1.5%). In our patient cohort, low-dose TMP-SMX preserves the efficacy of PJP prophylaxis while providing an acceptable adverse effect profile.

Immunotherapy in advanced cutaneous squamous cell carcinoma: Sydney west cancer network experience.

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the Caucasian population. A minority of cases are inoperable at presentation, recur or develop metastatic disease with a historical 5-year overall survival of ~10%. Treatment options in this setting are generally palliative. Immunotherapy has emerged as a new paradigm in managing these patients. Patients presenting to Sydney West Cancer Network with locally advanced or metastatic CSCC treated with the anti-PD1 agent cemiplimab were identified. Response to treatment was objectively assessed based on RECIST1.1 or PERCIST criteria. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), therapy toxicity, and predictors of treatment response. A total of 19 patients were identified with a median age of 76 (range 56-94) and 4 immunosuppressed. The longest follow up duration was 28 months. ORR, complete response (CR), and partial response (PR) were 68% (13/19), 53% (10/19), and 16% (3/19), respectively. Median PFS was 12 months (95% CI 9-14) whilst median OS was not reached by end of study. Responders (CR or PR) had significantly superior OS compared to those with no response (P < 0.01). A primary site of head and neck cancer was significantly associated with ORR (P=0.04). A single patient experienced Grade 3 toxicity with the rest being Grades 0-1. This study confirms the clinical efficacy of cemiplimab in patients with advanced CSCC with many experiencing a durable response and an acceptable adverse effect profile.

Research Highlights

Research Highlights

Clinical Review on the Utility of Fecal Microbiota Transplantation in Immunocompromised Patients.

Fecal microbiota transplantation (FMT) represents a promising management modality for Clostridium difficile infection (CDI). In immunocompromised patients, FMT is utilized for CDI as well as emerging non-CDI indications such as inflammatory bowel disease and graft versus host disease. PURPOSE OF REVIEW: This review aims to shed light on the safety and efficacy of FMT in immunocompromised patients, including patients suffering for human immunodeficiency virus infection, solid organ and hematopoietic stem cell transplant recipients, cancer patients, and patients on immunosuppressive therapies. RECENT FINDINGS: Though the body of evidence concerning the use of FMT in immunocompromised is growing, no clinical trials exist to date. Present literature weighs in favor of FMT in immunocompromised patients, with an acceptable adverse effect profile and minimal risk of infectious adverse events. Further large scale studies and randomized controlled trials to validate the utility of FMT in immunocompromised individuals will be a welcomed endeavor.

Motor outcome and electrode location in deep brain stimulation in Parkinson's disease.

ObjectivesTo evaluate the efficacy and adverse effects of subthalamic deep brain stimulation (STN‐DBS) in patients with advanced Parkinson's disease (PD) and the possible correlation between electrode location and clinical outcome.MethodsWe retrospectively reviewed 87 PD‐related STN‐DBS operations at Helsinki University Hospital (HUH) from 2007 to 2014. The changes of Unified Parkinson's Disease Rating Scale (UPDRS) part III score, Hoehn & Yahr stage, antiparkinson medication, and adverse effects were studied. We estimated the active electrode location in three different coordinate systems: direct visual analysis of MRI correlated to brain atlas, location in relation to the nucleus borders and location in relation to the midcommisural point.ResultsAt 6 months after operation, both levodopa equivalent doses (LEDs; 35%, Wilcoxon signed‐rank test = 0.000) and UPDRS part III scores significantly decreased (38%, Wilcoxon signed‐rank test = 0.000). Four patients (5%) suffered from moderate DBS‐related dysarthria. The generator and electrodes had to be removed in one patient due to infection (1%). Electrode coordinates in the three coordinate systems correlated well with each other. On the left side, more ventral location of the active contact was associated with greater LED decrease.ConclusionsSTN‐DBS improves motor function and enables the reduction in antiparkinson medication with an acceptable adverse effect profile. More ventral location of the active contact may allow stronger LED reduction. Further research on the correlation between contact location, clinical outcome, and LED reduction is warranted.

A Novel Use of Olaparib for the Treatment of Metastatic Castration-Recurrent Prostate Cancer.

Although mortality from prostate cancer has declined over the past 20years as a result of early detection and treatment, the 5-year survival rate for men with prostate cancer who develop metastatic disease is only 29%. Current treatment options for metastatic castration-recurrent prostate cancer (mCRPC) are associated with toxicity and a limited durable response; therefore, additional lines of efficacious and minimally toxic therapy are needed. Olaparib, a poly(adenosine 5'-diphosphate) ribose polymerase (PARP) inhibitor, received a U.S. Food and Drug Administration breakthrough therapy designation in January 2016 for the treatment of patients with BRCA1/2 or ATM gene-mutated mCRPC based on results of a compelling phase II trial of olaparib in patients with advanced castration-resistant prostate cancer (TOPARP-A). This study found that men with mCRPC and genetic mutations in DNA damage repair genes had an overall response rate of nearly 90% with olaparib treatment. In this review, we describe current therapies for mCRPC, the rationale for anti-PARP therapies, the pharmacology of olaparib for prostate cancer, clinical trials of olaparib for mCRPC, our clinical experience with olaparib for prostate cancer at a comprehensive cancer center, and future directions of olaparib for the treatment of mCRPC. Olaparib may constitute a promising treatment to prolong survival in patients with mCRPC, with an acceptable adverse effect profile. As the role of PARP inhibition in prostate cancer and other malignancies becomes further elucidated, olaparib may be shown to be beneficial for other patient populations.

Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies.

To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration-approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

Langerhans Cell Sarcoma: Treatment with Dose-adjusted EPOCH

Background: Langerhans cell sarcoma (LCS) is a rare malignancy with no specific defined treatment strategy.Chemotherapy is the preferred option in cases with systemic involvement, though no consensus exists on thepreferred regimen. Case: A sixty-six year old male presented with advanced-stage LCS involving the bone marrow (BM) and spleen. Immunohistochemical analysis of the BM-sample confirmed the diagnosis of LCS. The patient was treated withchemotherapy utilizing dose-adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin (DAEPOCH). The patient achieved complete remission and was able to tolerate the entire course (6 cycles) of chemotherapy with continued response at 10 months. Conclusion: Due to the rarity of the disease no standard treatment modality exists; most successful treatment options described are anecdotal reports. Due to the paucity of such data and inability to include enough patients on clinical trials, various combination chemotherapy options have been used for best clinical response. The unattractive response rate to CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) in previously described case series and the benefit of Etoposide in treating Langerhans cell histiocytosis and primitive sarcoma regimens along with an acceptable adverse effect profile, had us chose DA-EPOCH for our patient. We demonstrate that DAEPOCH is a tolerable and an efficacious treatment regimen for LCS.

Opioid Rotation in Clinical Practice

Although chronic opioid therapy is usually initiated using short-acting opioids, many patients with chronic pain are subsequently converted to long-acting and extended-release preparations. In clinical practice, optimal management requires careful individualization of dosage in order to achieve an appropriate balance of efficacy and adverse effects. After successful initiation and stabilization of opioid treatment, subsequent changes in regimen may still be required to maintain efficacy with an acceptable adverse effect profile. This is a qualitative review of the available literature from June 2012 or earlier on opioid rotation for the management of chronic pain in the clinical setting. The PubMed database was searched using various search terms, and additional articles were identified through manual search of the bibliographies of articles identified through the PubMed search. Papers were selected based on relevance to the topic. When considering opioid rotation, clinicians must take into account not only the significant differences in potency among opioid drugs but also the considerable interpatient variability in response to opioids. The estimate of relative potency used in calculating an appropriate starting dose when switching from one opioid to another has been codified on equianalgesic dose tables. To reduce the risk of unintentional overdose, a two-step calculation has been proposed, which incorporates an initial reduction (typically 25-50%) in the equianalgesic dose followed by a second evaluation based on the severity of pain at the time of rotation along with other medical or psychosocial factors that might alter the effectiveness and tolerability of the new drug. Given the uncertainty of accurately predicting a patient's response to treatment, each initial exposure to a new opioid should be considered a discrete clinical trial to assess the degree of response. Systematic reviews of opioid rotation have documented the re-establishment of adequate pain control or reduced adverse effects in 50-80% of patients. Although continued research is needed to refine equianalgesic doses further, opioid rotation is an important and necessary practice in patients with chronic cancer or noncancer pain that is refractory to the initially used opioid.

Liposomal bupivacaine: a review of a new bupivacaine formulation

Many attempts have been made to increase the duration of local anesthetic action. One avenue of investigation has focused on encapsulating local anesthetics within carrier molecules to increase their residence time at the site of action. This article aims to review the literature surrounding the recently approved formulation of bupivacaine, which consists of bupivacaine loaded in multivesicular liposomes. This preparation increases the duration of local anesthetic action by slow release from the liposome and delays the peak plasma concentration when compared to plain bupivacaine administration. Liposomal bupivacaine has been approved by the US Food and Drug Administration for local infiltration for pain relief after bunionectomy and hemorrhoidectomy. Studies have shown it to be an effective tool for postoperative pain relief with opioid sparing effects and it has also been found to have an acceptable adverse effect profile. Its kinetics are favorable even in patients with moderate hepatic impairment, and it has been found not to delay wound healing after orthopedic surgery. More studies are needed to establish its safety and efficacy for use via intrathecal, epidural, or perineural routes. In conclusion, liposomal bupivacaine is effective for treating postoperative pain when used via local infiltration when compared to placebo with a prolonged duration of action, predictable kinetics, and an acceptable side effect profile. However, more adequately powered trials are needed to establish its superiority over plain bupivacaine.

Combination of Low-Dose Isotretinoin and Pulsed Oral Azithromycin in the Management of Moderate to Severe Acne

The conventionally used dose of isotretinoin in acne causes significant dose-related adverse effects. Low-dose isotretinoin has been used successfully in mild to moderate papulopustular acne. Although isotretinoin acts against all mechanisms of acne formation, it has no significant direct antimicrobial effect. To test whether the addition of an antibacterial enables use of isotretinoin in low doses even in moderate to severe acne. This was a preliminary open-label, prospective, non-comparative, single-centre study carried out in a tertiary-care referral hospital. Seventy patients with grade 3 and 4 acne according to the US FDA global score were included in the study between October 2005 and December 2007. These patients were treated with a combination of low-dose isotretinoin (0.3 mg/kg/day) and pulsed oral azithromycin (500 mg/day over three consecutive days every 2 weeks). Response to treatment was assessed at monthly intervals and was recorded as a percentage decrease in overall severity of disease. Treatment was continued to complete clearance of lesions or to 16 weeks, whichever came later. Sixty-two (93.9%) of 66 eligible patients had complete clearance of disease activity after a mean treatment duration of 21 weeks. The mean total cumulative dose of isotretinoin was 49.6 mg/kg. Seven (11.3%) patients had a relapse of disease during the post-treatment follow-up period. Fifty-three adverse effects were observed. Three patients had initial aggravation of disease that was managed with prednisolone and disappeared with continuation of treatment. A combination of low-dose isotretinoin and oral azithromycin pulse is effective in severe acne and has a reasonably acceptable adverse-effect profile and low post-treatment relapse rates.

Emerging therapies for treatment of multiple sclerosis

In the last decade, a new armamentarium of immune-based therapies have been developed and tested in patients with multiple sclerosis. Some of these therapies are showing a high level of efficacy, with an acceptable adverse effect profile. Because present therapies have significant limitations in slowing disease progression, require injections, are sometimes associated with significant side effects of immunosuppression, and do little to reverse disability, identifying more effective treatments is an important goal for clinical research in multiple sclerosis. However, in order to improve our current approach to disease-modifying therapies, it is imperative to promote the development of individualized therapy strategies.

Role of Interleukin-2 in Patients with HIV Infection

Control of viral replication to below the level of quantification using combination antiretroviral therapy (ART) [cART] has led to a dramatic fall in mortality and morbidity from AIDS. However, despite the success of cART, it has become apparent that many patients do not achieve normalized CD4+ T-cell counts despite virological suppression to below the level of quantification (<50 copies/mL). Increasing data from cohort studies and limited data from clinical trials, such as the SMART study, have shown that higher CD4+ T-cell counts are associated with reductions in morbidity and mortality from both AIDS and serious non-AIDS (SNA) conditions, including cardiovascular disease. Enhancement of immune restoration over and above that achievable with ART alone, using a number of strategies including cytokine therapy, has been of interest for many years. The most studied cytokine in this setting is recombinant interleukin (IL)-2 (rIL-2). The purpose of this review is to describe the current status of rIL-2 as a therapeutic agent in the treatment of HIV-1 infection. The review focuses on the rationale underpinning the exploration of rIL-2 in HIV infection, summarizing the phase II and III findings of rIL-2 as an adjunctive therapy to ART and the phase II studies of rIL-2 as an antiretroviral-sparing agent. The phase II studies demonstrated the potential utility of continuous intravenous IL-2 and subsequently intermittent dosing with subcutaneous rIL-2 as a cytokine that could expand the CD4+ T-cell pool in HIV-1-infected patients without any significant detrimental effect on HIV viral load and with an acceptable adverse-effect profile. These data were utilized in designing the phase II studies of rIL-2 as an ART-sparing agent and, more importantly, the large phase III clinical endpoint studies of rIL-2 in HIV-1-infected adults, ESPRIT and SILCAAT. In the latter, subcutaneous rIL-2 was given intermittently (5 days of twice-daily dosing at 4.5-7.5 million international units per dose every 8 weeks) to HIV-1-infected adults receiving cART using an induction/maintenance strategy. Both studies explored the clinical benefit of intermittent subcutaneous rIL-2 with cART versus cART in HIV-infected adults with CD4+ T-cell counts > or = 300 cells/microL (ESPRIT study) and 50-299 cells/microL (SILCAAT study). Both studies showed that receipt of rIL-2 conferred no clinical benefit despite a significantly higher CD4+ T-cell count in the rIL-2 arms of both studies. Moreover, there was an excess of grade 4 clinical events in ESPRIT rIL-2 recipients. The results of the phase III clinical endpoint studies showed that rIL-2 has no place as a therapeutic agent in the treatment of HIV infection.

Bedtime Administration of Graded-Release Diltiazem in Patients with Inadequate BP Control

Achievement of target BP is a challenge in patients attending family practice. The long duration between administration of the last bedtime dose of antihypertensive medication and the physiologic early morning surge in BP makes it difficult to achieve satisfactory BP control. To determine whether a new graded-release preparation of diltiazem (diltiazem XC), taken once daily at bedtime, will show an acceptable adverse-effect profile as well as improved BP control. This is an open label, observational study in an ambulatory care setting. 954 patients with mild to moderate hypertension and BP not at target levels were attended by 85 physicians. Group 1 patients were receiving a diltiazem preparation and group 2 patients were not receiving any diltiazem preparation at baseline. Group 1 patients were given diltiazem XC at the same dose as the prestudy diltiazem. Treatment with diltiazem XC 180 mg was initiated in group 2 patients. Diltiazem XC was taken once daily at bedtime in both groups. The predetermined main outcome measure was the development of adverse events with diltiazem XC when changing or adding the study medication. The secondary outcome measure was the proportion of patients who achieved target BP levels. Moderate or severe adverse events occurred in 8.7% of patients. Although 21.8% of patients reported either new or worsening adverse events after starting diltiazem XC, the large majority of adverse events were mild in severity. The most frequent moderate or severe adverse events were headache (2.0%) and constipation (1.7%). More patients in group 2 reported adverse events compared with patients in group 1. Target BP levels were achieved in 47.8% (95% CI 44.3, 51.3) of patients completing the 8- to 12-week treatment. No difference was found in the proportion of patients at target BP levels in groups 1 and 2. Diltiazem XC, when used in an ambulatory care setting for patients who have not achieved BP targets, shows an acceptable adverse-effect profile and results in an important improvement of BP control.

Lyme disease prevention and vaccine prophylaxis.

To provide a comprehensive review of the epidemiology, diagnosis, and prevention of Lyme disease with a focus on the Lyme disease vaccine. A computerized search of MEDLINE (January 1996-December 1998) was used to identify articles regarding Lyme disease, Borrelia burgdorferi, epidemiology, prevention, and vaccine. Lyme disease is a condition caused by infection with B. burgdorferi. The organism is carried by certain species of Ixodes ticks and is the most common tick-borne disease in the US. In patients with clinical manifestations of Lyme disease, various pharmacotherapeutic approaches have proven effective in treatment of the clinical features. Prevention strategies exist; however, their application is sometimes difficult. A vaccine for the prevention of Lyme disease is available, and another is being considered for approval. The recombinant outer surface protein A (OspA) vaccines to prevent Lyme disease are immunogenic and have an acceptable adverse effect profile. These vaccines are highly efficacious for the prevention of Lyme disease. Lyme disease is the most common tick-borne disease in the US. The infection, caused by B. burgdorferi, results in dermatologic, neurologic, cardiovascular, and musculoskeletal manifestations. Until recently, tick bite prevention strategies were the only means of decreasing the risk of acquiring the infection. The OspA vaccines are efficacious for the prevention of infection. Although universal immunization with these vaccines is unlikely, the availability of effective vaccines represents an important tool for the prevention of Lyme disease in endemic regions of the US.

Metronidazole. A therapeutic review and update.

The nitroimidazole antibiotic metronidazole has a limited spectrum of activity that encompasses various protozoans and most Gram-negative and Gram-positive anaerobic bacteria. Metronidazole has activity against protozoans like Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis, for which the drug was first approved as an effective treatment. Anaerobic bacteria which are typically sensitive are primarily Gram-negative anaerobes belonging to the Bacteroides and Fusobacterium spp. Gram-positive anaerobes such as peptostreptococci and Clostridia spp. are likely to test sensitive to metronidazole, but resistant isolates are probably encountered with greater frequency than with the Gram-negative anaerobes. Gardnerella vaginalis is a pleomorphic Gram-variable bacterial bacillus that is also susceptible to metronidazole. Helicobacter pylori has been strongly associated with gastritis and duodenal ulcers. Classic regimens for eradicating this pathogen have included metronidazole, usually with acid suppression medication plus bismuth and amoxicillin. The activity of metronidazole against anaerobic bowel flora has been used for prophylaxis and treatment of patients with Crohn's disease who might develop an infectious complication. Treatment of Clostridium difficile-induced pseudomembraneous colitis has usually been with oral metronidazole or vancomycin, but the lower cost and similar efficacy of metronidazole, coupled with the increased concern about imprudent use of vancomycin leading to increased resistance in enterococci, have made metronidazole the preferred agent here. Metronidazole has played an important role in anaerobic-related infections. Advantages to using metronidazole are the percentage of sensitive Gram-negative anaerobes, its availability as oral and intravenous dosage forms, its rapid bacterial killing, its good tissue penetration, its considerably lower chance of inducing C. difficile colitis, and expense. Metronidazole has notable effectiveness in treating anaerobic brain abscesses. Metronidazole is a cost-effective agent due to its low acquisition cost, its pharmacokinetics and pharmacodynamics, an acceptable adverse effect profile, and its undiminished antimicrobial activity. While its role as part of a therapeutic regimen for treating mixed aerobic/anaerobic infections has been reduced by newer, more expensive combination therapies, these new combinations have not been shown to have any therapeutic advantage over metronidazole. Although the use of metronidazole on a global scale has been curtailed by newer agents for various infections, metronidazole still has a role for these and other therapeutic uses. Many clinicians still consider metronidazole to be the 'gold standard' antibiotic against which all other antibiotics with anaerobic activity should be compared.

Colchicine prophylaxis in familial Mediterranean fever: Reappraisal after 15 years

As determined in this study of 45 patients, the prolonged use of colchicine therapy in familial Mediterranean fever (FMF) is safe and effective in preventing flares of FMF and amyloidosis. It has an acceptable adverse effect profile and can be used in children and pregnant women. Its discontinuation predisposes patients to acute FMF attacks and the development of amyloidosis. Articular involvement is less responsive to colchicine and may require therapy with nonsteroidal antiinflammatory drugs.