Chronic High-dose Use Research Articles

Use, Misuse and Abuse of Testosterone and Other Androgens.

For several decades, testosterone and its synthetic derivatives have been used for anabolic and androgenic purposes. Initially restricted to professional bodybuilders, these substances gradually became more popular with recreational weightlifters. Considering its increasing prevalence, the consumption of anabolic androgenic steroids (AAS) has become a matter of great concern. Although most side effects are mild and reversible, some of them can cause permanent damage or can be potentially life threatening. To review and summarize medical literature regarding misuse and abuse of testosterone and other androgens, in order to provide evidence-based information on the main topics related to this subject, such as how to identify and how to deal with these patients, and to elucidate the multiple possible adverse effects secondary to this practice. Key studies were retrieved from PubMed (1989-2021) with reference searches from relevant articles. Search terms included "hypogonadism", "anabolic androgenic steroids", "androgens", "misuse AND testosterone", "abuse AND testosterone", and "side effects AND testosterone". There is a significant lack of information in the peer-reviewed literature describing demographic data, implications for different organ systems and the management of current or former AAS users; however, androgen abuse has been already linked to a wide variety of cardiovascular diseases, metabolic, endocrine, neurological, psychiatric and liver disorders. Despite all this, most physicians still feel uncomfortable and hesitate to discuss the issue with patients. The chronic use of high doses of AAS is associated with adverse effects in several organ systems; however, there are still many gaps in our knowledge about the long-term consequences of this practice and how to deal with these patients. Healthcare professionals have a crucial role in combating this public health problem, recognizing and preventing the spread of androgen abuse.

Intervention by Post for Reducing the Chronic Use of High Doses of Proton Pump Inhibitors

Intervention by Post for Reducing the Chronic Use of High Doses of Proton Pump Inhibitors

Secondary Adrenal Insufficiency Is Associated with Poor Survival Outcomes in Multiple Myeloma

Background: Glucocorticoids has been a backbone of various treatment regimens for multiple myeloma (MM). The repeated and chronic use of high doses of glucocorticoids is associated with development of secondary adrenal insufficiency (AI), and AI could be a major problem in critically-ill patients. However, there has been no specialized data about incidence and clinical significance of secondary AI in hospitalized patients with MM.Purpose: The objective of this retrospective study is to evaluate incidence, predictive factors, and clinical significance of secondary AI in hospitalized patients with MM.Methods: We retrospectively evaluated medical records of MM patients who were hospitalized in Chonnam National University Hwasun Hospital, South Korea from December 2014 to December 2015. The definite AI was diagnosed when the peak cortisol concentration was less than < 500 nmol/L (18 mcg/dL) after ACTH administration.Results: Between December 2014 and December 2015, 77 patients were hospitalized, and 58 underwent rapid ACTH stimulation test. The most frequent cause of hospitalization was infection (70.7%), followed by weakness (24.1%), and the others (5.3%). The definite AI was confirmed in 19 patients (32.7%). To evaluate the predictive factors of AI, all variables including clinical characteristics, laboratory results, cumulative steroid dose, and treatment duration at hospitalization were analyzed, but there were no significant predictors for AI. In addition, the patients with AI had a significantly poor survival outcomes compared to those without AI (the median overall survival of 42.3 months vs. 82.7 months; P = 0.037) (Figure 1).Conclusions: This study showed that the secondary AI is not a rare condition among hospitalized patients with MM, and there was no specific predictable symptoms or signs. In addition, development of AI in the treatment period is associated with a poor prognosis. This study suggests that evaluation of AI is routinely needed in hospitalized patients with MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study.

Although mortality related to psychotropic medications has received much attention in recent years, little is known about the relationship between risk of death and cumulative antipsychotic load, and even less about the relationship between mortality and cumulative exposure to antidepressants or benzodiazepines. The authors examined these relationships using nationwide databases. The authors used prospectively collected nationwide databases to identify all individuals 16-65 years of age with a schizophrenia diagnosis (N=21,492) in Sweden. All-cause and cause-specific mortality rates were calculated as a function of cumulative low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines from 2006 through 2010. Compared with no exposure, both moderate (adjusted hazard ratio=0.59, 95% CI=0.49-0.70) and high (adjusted hazard ratio=0.75, 95% CI=0.63-0.89) antipsychotic exposures were associated with substantially lower overall mortality. Moderate antidepressant exposure was associated with a lower mortality (adjusted hazard ratio=0.85, 95% CI=0.73-0.98), and high exposure, even lower (adjusted hazard ratio=0.71, 95% CI=0.59-0.86). Exposure to benzodiazepines showed a dose-response relationship with mortality (hazard ratios up to 1.74 [95% CI=1.50-2.03]). Moderate and high-dose antipsychotic and antidepressant use were associated with 15%-40% lower overall mortality, whereas chronic high-dose use of benzodiazepines was associated with up to a 70% higher risk of death compared with no exposure. Since patients with anxiety and depressive symptoms may have a higher intrinsic risk of death, the finding for benzodiazepines may be attributable to some extent to residual confounding.

Quais são e pra que servem os medicamentos à base de Cannabis?

The Cannabis is constituted by compounds with therapeutic properties, obsered in distinct contexts. Some Cannabis-based products are already available in the international market, and here we will highlight those already in use, which are supported by solid scientific evidence, including phytocannabinoids, synthetic cannabinoids and herbal extracts. The biggest challenge is to balance the beneficial effects of Cannabis and the potential adverse effects, which may happen after chronic high-dose use. Despite the equivalente efficacy, smoked Cannabis is not well tolerated by patients without previous recreative use. On the other hand, the herbal product is preferred by recreative users that become patients. In this case, one should vaporize the plant, to avoid the harms caused by the smoke. Considering cost-effectiveness, therapeutic efficacy and quality control, the standardized herbal extracts seem to be the best option, so far available.

AB0734 Assessment of Spondyloarthritis Patients Bone Health by Trabecular Bone Score (TBS): A Pilot Study

BackgroundPatients with spondyloarthritis (SpA) have an elevated incidence of osteoporosis and are at increased risk of pathological vertebral fracture. Evaluation of bone by dual energy X-Ray absorptiometry (DXA) has its...

Toxic hepatitis induced by a herbal medicine: Tinospora crispa

Herbal remedies are becoming increasingly popular in many countries. Tinospora species (Menispermaceae) is commonly used as a herbal medicine in South Asia, but very few toxic effects have been described. We report a case of acute hepatitis associated with chronic use of high doses of Tinospora crispa.A 49-year-old male with chronic low back pain bought a herbal medicine at a market in Vietnam that was supposed to be Tinospora crispa, and started to take 10 pellets per day. He had no medical history and did not take any other drugs or toxins. Four weeks later; he developed dark urine and pale stools, associated with asthenia and right hypochondrial pain. Two months after starting treatment, he was referred to the hepatology department with jaundice. Blood tests showed aspartate aminotransferase: 1.169IU/l, alanine aminotransferase: 2.029IU/l, total bilirubin: 20.47mg/dl, direct bilirubin: 13.29mg/dl, and γ-glutamyltransferase: 243IU/l. Viral and autoimmune hepatitis were eliminated. Upper abdominal ultrasound was normal. Histopathological findings were consistent with a toxic reaction. The herbal medicine was stopped on admission and the patient fully recovered without treatment, with normal liver function 2 months after the acute episode. Tinospora crispa was clearly identified in the pellets by microscopic analysis of the botanical characters combined with chromatographic fingerprints.The use of herbal medicines containing Tinospora crispa can induce toxic hepatitis. Recovery can be complete after discontinuation. This case highlights the risk associated with traditional herbal remedies.

Timeline: kisspeptins

Kisspeptins are peptides encoded by KISS1. The gene was first discovered in 1996, in Hershey, PA, USA, and was subsequently named after Hershey's chocolate kisses. The peptide product of KISS1 is a 145 aminoacid peptide that is cleaved into four shorter peptides: kisspeptin-54, kisspeptin-14, kisspeptin-13, and kisspeptin-10 (the numbers denote how many aminoacids in each). All these isoforms activate the kisspeptin receptor. Kisspeptins produced in the hypothalamus stimulate neurons in the hypothalamus that secrete gonadotropin-releasing hormone (GnRH), which subsequently stimulates release of gonadotropins and sex steroid hormones. Kisspeptin has been shown to have a crucial role in puberty. Inactivating mutations of the kisspeptin receptor or KISS1 gene lead to pubertal failure due to hypogonadotrophic hypogonadism in mice and in people. Conversely, activating mutations of the kisspeptin receptor in people lead to central precocious puberty. Exogenous kisspeptin stimulates gonadotropin release in all animal species studied and in people. This effect is mediated predominantly by stimulating GnRH release (because pretreatment with a GnRH antagonist completely blocks the ability of kisspeptin to stimulate gonadotropin release). Recent evidence also suggests that the kisspeptin system is important in the generation of GnRH pulses, which are crucial for normal fertility. In a subpopulation of neurons in the hypothalamic arcuate nucleus, kisspeptin colocalises with two other hormones known to affect GnRH release, namely neurokinin B (NKB) and dynorphin (DYN). This group of cells is often referred to as the KNDy neurons. Increasing data suggest that KNDy neurons have a key role in mediation of pulsatile GnRH release. Evidence thus far suggests that kisspeptin has exciting therapeutic potential in people—eg, acute use of kisspeptin for infertility could stimulate reproductive hormone release more naturally than by conventional methods. Data for human beings also suggest that kisspeptin might stimulate pulses of luteinising hormone, indicating its therapeutic potential for the treatment of women with anovulatory infertility. Chronic use of high doses of kisspeptin causes desensitisation and reduces secretion of gonadotropins. Hence, longacting forms of kisspeptin are being developed to treat hormone-sensitive cancers, with promising early results in people.

What Is the Lethal Concentration of Hydrocodone?

Hydrocodone is a semisynthetic opioid medication that is widely used as an analgesic and antitussive. Since 2004 it has been the most commonly prescribed drug in the United States and is often misused as a drug of abuse. Hydrocodone is frequently encountered in the postmortem setting, both as a cause of death and incidentally. Unfortunately, information regarding the concentrations of hydrocodone found with chronic high-dose use is lacking, and interpretation of postmortem concentrations can be difficult. A retrospective review of postmortem and "Driving under the Influence" (DUI) cases in Bexar County Texas in which hydrocodone was present was conducted. The cases were included in the study if they fit the criteria of belonging to 1 of 3 categories: the hydrocodone either caused or was the main contributor to death; the hydrocodone was incidental and definitively did not cause or contribute to death; and the DUI cases. The average hydrocodone concentration in the cases where the hydrocodone caused death was 0.47 mg/L (median, 0.38 mg/L). The average hydrocodone concentration in cases where it was incidental to death was 0.15 mg/L (median, 0.08 mg/L). The average hydrocodone concentration in the DUI cases was 0.09 mg/L (median, 0.08 mg/L). Analysis showed the possibility of postmortem redistribution as well as significant overlap of the concentrations noted in the different groups. Given that no definitive lethal concentration could be delineated, it is recommended that each hydrocodone case encountered be assessed individually to include a thorough medical record review to accurately interpret hydrocodone concentrations. It has also been shown that concentrations as high as 0.3 mg/L peripherally and 1.4 mg/L centrally can be present and not result in death. In addition, further research into hydrocodone concentrations with chronic use and hydrocodone metabolism is necessary.

Hydropic decompensation with hyponatraemia in patients awaiting cardiac transplantation – effect of the calcium sensitizer levosimendan

Introduction: Hydropic decompensation in chronic heart failure patients (pts) associated with severe hyponatraemia due to chronic use of high doses of loop diuretics is a special therapeutic challenge. The aim of this case series was to evaluate the hemodynamics and renal effects of levosimendan in this setting.

Chemoprevention of Familial Adenomatous Polyposis by Low Doses of Atorvastatin and Celecoxib Given Individually and in Combination to APCMin Mice

Preclinical and clinical studies have established evidence that cyclooxygenase-2 (COX-2) inhibitors and statins [hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors] inhibit colon carcinogenesis. Chronic use of high doses of COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of atorvastatin (Lipitor) and celecoxib individually or in combination in an animal model of familial adenomatous polyposis. Six-week-old male C57BL/6J-APCmin/+ mice were either fed diets containing 0 or 100 ppm atorvastatin or 300 ppm celecoxib, or a combination of both for approximately 80 days. Mice were sacrificed, and their intestines were scored for tumors. Normal-seeming mucosa and intestinal tumors were harvested and assayed for apoptosis (terminal deoxynucleotidyl transferase-mediated nick-end labeling) and HMGR and COX-2 protein expression and activity. We observed that 100 ppm atorvastatin significantly (P < 0.002) suppressed intestinal polyp formation. As anticipated, 300 ppm celecoxib decreased the rate of formation of intestinal polyps by approximately 70% (P < 0.0001). Importantly, the combination of 100 ppm atorvastatin and 300 ppm celecoxib in the diet suppressed the colon polyps completely and small intestinal polyps by >86% (P < 0.0001) compared with the control group. The inhibition of tumor formation by the atorvastatin and celecoxib combination was significant (P < 0.005) when compared with tumor inhibition by celecoxib alone. In addition, increased rates of apoptosis in intestinal tumors (P < 0.01-0.0001) were observed in animals fed with atorvastatin and celecoxib and more so with the combinations. Tumors of animals fed atorvastatin showed a significant decrease in HMGR-R activity. Similarly, tumors of mice exposed to celecoxib showed significantly lower levels of COX-2 activity. These observations show that atorvastatin inhibits intestinal tumorigenesis and that, importantly, when given together with low doses of celecoxib, it significantly increases the chemopreventive efficacy in an APC(min) mice.

Prevention of Azoxymethane-Induced Colon Cancer by Combination of Low Doses of Atorvastatin, Aspirin, and Celecoxib in F 344 Rats

Preclinical and clinical studies have provided evidence that aspirin, celecoxib, (cyclooxygenase-2 inhibitor), and statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) inhibit colon carcinogenesis. Chronic use of high doses of these agents may induce side effects in ostensibly normal individuals. Combining low doses of agents may be an effective way to increase their efficacy and minimize toxicity. We assessed the efficacy of atorvastatin (lipitor), celecoxib, and aspirin, given individually at high dose levels and in combination at lower doses against azoxymethane-induced colon carcinogenesis, in male F 344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight, s.c., once weekly for 2 weeks), groups of male F 344 rats were fed the AIN-76A diet or AIN-76A diet containing 150 ppm atorvastatin, 600 ppm celecoxib, and 400 ppm aspirin, 100 ppm atorvastatin + 300 ppm celecoxib, and 100 ppm atorvastatin + 200 ppm aspirin. Rats were killed 42 weeks later, and colon tumors were processed histopathologically and analyzed for cell proliferation and apoptosis immunohistochemically. Administration of these agents individually and in combination significantly suppressed the incidence and multiplicity of colon adenocarcinomas. Low doses of these agents in combination inhibited colon carcinogenesis more effectively than when they were given individually at higher doses. Inhibition of colon carcinogenesis by these agents is associated with the inhibition of cell proliferation and increase in apoptosis in colon tumors. These observations are of clinical significance because this can pave the way for the use of combinations of these agents in small doses against colon cancer.

Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers

Preclinical investigations have established that methamphetamine (MA) produces long-term changes in dopamine (DA) neurons in the striatum. Human studies have suggested similar effects and correlated motor and cognitive deficits. The present study was designed to further our understanding of changes in brain function in humans that might result from chronic high dose use of MA after at least 3 months of abstinence. Brain function in abstinent users was compared to controls using neuroimaging of monoamine transporters and cognitive assessment. Striatal levels of DA transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined using [11C]methylphenidate and [11C]dihydrotetrabenazine positron emission tomography, respectively. Cognitive function was evaluated using tests of motor function, memory, learning, attention, and executive function. Striatal DAT was approximately 15% lower and VMAT2 was 10% lower in MA abusers across striatal subregions. The MA abusers performed within the normal range but performed more poorly compared to controls on three of the 12 tasks. Failure to find more substantial changes in transporter levels and neurocognitive function may be attributed to the length of time that MA users were abstinent (ranging from 3 months to more than 10 years, mean 3 years), although there were no correlations with length of abstinence. Persistent VMAT2 reductions support the animal literature indicating a toxic effect of MA on nigrostriatal nerve terminals. However, the magnitude of the MA effects on nigrostriatal projection integrity is sufficiently small that it is questionable whether clinical signs of DA deficiency are likely to develop.

High frequency of use of rofecoxib at greater than recommended doses: cause for concern.

To determine the prevalence of chronic use of rofecoxib 50 mg. Rofecoxib is unusual among nonsteroidal anti-inflammatory drugs (NSAIDs) in that the licensed dose for acute pain is double the maximum dose recommended for chronic use. The 50 mg dose is recommended for acute pain only, for a maximum of 5 days. In clinical trials of chronic use for arthritis, hypertension was more frequent in patients assigned 50 mg rofecoxib than in those assigned lower doses or other NSAIDs. Thus chronic use of high doses of rofecoxib has implications for patient safety. Cross-sectional analysis of the prevalence of chronic use of rofecoxib 50 mg in 2001, among persons aged > or =50 years, enrolled in the Tennessee Medicaid program. On 1 July 2001, 14% of the study population had a current prescription for an NSAID, with a supply of pills for >5 days. Of all NSAID prescriptions, 25% were for rofecoxib, and 17% of these prescriptions were for >25 mg daily. Of those prescribed >25 mg daily, 71% filled prescriptions for at least 50 mg for 30 days. In this latter group, 60% and 69% filled another rofecoxib prescription within 1 and 2 weeks, respectively, of the end of their 30 days supply. Demographics and co-morbid conditions of high dose rofecoxib users did not differ substantially from users of other NSAIDs or the total population. Use of rofecoxib 50 mg for >5 days is relatively common. In view of dose-related adverse effects, such use should be discouraged.

Delta9-tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect.

Recent studies have suggested that cannabinoids might initiate the consumption of other highly addictive substances, such as opiates. In this work, we show that acute administration of Delta9-tetrahydrocannabinol in mice facilitates the antinociceptive and antidepressant-like responses elicited by the endogenous enkephalins protected from their degradation by RB 101, a complete inhibitor of enkephalin catabolism. This emphasizes the existence of a physiological interaction between endogenous opioid and cannabinoid systems. Accordingly, Delta9-tetrahydrocannabinol increased the release of Met-enkephalin-like material in the nucleus accumbens of awake and freely moving rats measured by microdialysis. In addition, this cannabinoid agonist displaced the in vivo [3H]diprenorphine binding to opioid receptors in total mouse brain. The repetitive pretreatment during 3 weeks of Delta9-tetrahydrocannabinol in mice treated chronically with morphine significantly reduces the naloxone-induced withdrawal syndrome. However, this repetitive administration of Delta9-tetrahydrocannabinol did not modify or even decrease the rewarding responses produced by morphine in the place preference paradigm. Taken together, these behavioural and biochemical results demonstrate the existence of a direct link between endogenous opioid and cannabinoid systems. However, chronic use of high doses of cannabinoids does not seem to potentiate the psychic dependence to opioids.

High-dose intravitreal ganciclovir and foscarnet for cytomegalovirus retinitis

PURPOSE: To describe the chronic use of high doses of intravitreal ganciclovir, in combination with foscarnet, for the treatment of cytomegalovirus retinitis. METHODS: A 31-year-old man with human immunodeficiency virus (HIV) infection and unilateral active cytomegalovirus retinitis was treated with escalating intravitreal injections of ganciclovir (up to 3.0 mg twice a week) in combination with foscarnet (up to 2.4 mg twice a week) over the course of approximately 1 year. RESULTS: Complete regression of the retinitis was obtained with high doses of intravitreal ganciclovir and foscarnet. Visual acuity in the affected eye remained 20/20 throughout the course of therapy. No ganciclovir retinal toxicity was identified. CONCLUSION: High doses of intravitreal ganciclovir in combination with foscarnet can be well tolerated and may be required to successfully control cytomegalovirus retinitis in some patients.