Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice

Benznidazole and nifurtimox, the only drugs available for the treatment of Chagas disease, have limited efficacy and have been associated with severe adverse side effects. Thus, there is an urgent need to find new biotargets for the identification of novel bioactive compounds against the parasite and with low toxicity. Silent information regulator 2 (Sir2) enzymes, or sirtuins, have emerged as attractive targets for the development of novel antitrypanosomatid agents. In the present work, we evaluated the inhibitory effect of natural compounds isolated from cashew nut (Anacardium occidentale, L. Anacardiaceae) against the target enzymes TcSir2rp1 and TcSir2rp3 as well as the parasite. Two derivates of cardol (1, 2), cardanol (3, 4), and anacardic acid (5, 6) were investigated. The two anacardic acids (5, 6) inhibited both TcSir2rp1 and TcSir2rp3, while the cardol compound (2) inhibited only TcSir2rp1. The most potent sirtuin inhibitor active against the parasite was the cardol compound (2), with an EC50 value of 12.25 µM, similar to that of benznidazole. Additionally, compounds (1, 4), which were inactive against the sirtuin targets, presented anti-T. cruzi effects. In conclusion, our results showed the potential of Anacardium occidentale compounds for the development of potential sirtuin inhibitors and anti-Trypanosoma cruzi agents.

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Editor's Preface: Antidepressants of the Future

The British Journal of Psychiatry ◽

10.1192/s0007125000297420 ◽

1989 ◽

Vol 155 (S6) ◽

pp. 7-8 ◽

Cited By ~ 2

Author(s):

R.G. Priest

Keyword(s):

Side Effects ◽

Limited Efficacy ◽

Treatment Of Depression ◽

The Future

Existing antidepressants are unsatisfactory: they have limited efficacy, side-effects are a problem, and there is an appreciable degree of toxicity. However, nonpharmacological, psychological approaches to the treatment of depression also have their own drawbacks, so that the search for better antidepressant compounds continues.

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DOLUTEGRAVIR efficacy in HIV infected patients

ARS Medica Tomitana ◽

10.1515/arsm-2015-0019 ◽

2015 ◽

Vol 21 (1) ◽

pp. 42-51

Author(s):

Irina Magdalena Dumitru ◽

Roxana Carmen Cernat ◽

S. Rugină

Keyword(s):

Side Effects ◽

Glucose Metabolism ◽

Bone Loss ◽

Opportunistic Infections ◽

Patient Adherence ◽

Fat Distribution ◽

Mortality And Morbidity ◽

The Past ◽

The World

Abstract In the past years there have been numerous discoveries regarding treatment of patients with HIV. If at first the doctors watched as patients live longer, now we want these patients to live better with regimens potent, safe, individualized and without side effects. HAART has revolutionized “the world HIV” and caused a significant reduction in mortality, and morbidity associated with HIV-related opportunistic infections. However, side effects associated with HAART, metabolic toxicity (such as abnormal fat distribution, abnormal lipid and glucose metabolism, and bone loss) and the large number of pills led to decreased patient adherence.

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Endocrine side effects of broad-acting kinase inhibitors

Endocrine Related Cancer ◽

10.1677/erc-10-0082 ◽

2010 ◽

Vol 17 (3) ◽

pp. R233-R244 ◽

Cited By ~ 45

Author(s):

Maya B Lodish ◽

Constantine A Stratakis

Keyword(s):

Targeted Therapy ◽

Side Effects ◽

Glucose Metabolism ◽

Cancer Therapy ◽

Fetal Development ◽

Linear Growth ◽

Kinase Inhibitors ◽

Mechanisms Of Action ◽

Cellular Level ◽

Gonadal Function

Targeted therapy in oncology consists of drugs that specifically interfere with abnormal signaling pathways that are dysregulated in cancer cells. Tyrosine kinase inhibitors (TKIs) take advantage of unique oncogenes that are activated in certain types of cancer, and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. However, many kinase inhibitors for cancer therapy are somewhat nonselective, and most have additional mechanisms of action at the cellular level, which are not completely understood. The use of these agents has increased our knowledge of important side effects, of which the practicing clinician must be aware. Recently, proposed endocrine-related side effects of these agents include alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, and glucose metabolism, and adrenal function. This review summarizes the most recent data on the endocrine side effects of TKIs.

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Medicinal plants with anticonvulsant activities with emphasis on their mechanisms of action

10.30574/ijbpsa.2021.1.2.0045 ◽

2021 ◽

Vol 1 (2) ◽

pp. 177-189

Author(s):

Ali Esmail Al-Snafi

Keyword(s):

Side Effects ◽

Medicinal Plants ◽

Antiepileptic Drugs ◽

Mode Of Action ◽

Refractory Epilepsy ◽

Mechanisms Of Action ◽

Active Ingredients ◽

Antiepileptic Activity ◽

Limited Efficacy ◽

Anticonvulsant Activities

A large percent of the patients were controlled by the available antiepileptic drugs. The limited efficacy of antiepileptic drugs is still a matter of concern, >30% of patients showed refractory epilepsy and 30-40% suffered from antiepileptic side effects. Many kinds of medicinal plants possessed antiepileptic activity, and many researchers have focused on the efficacy of their crude extracts. This review discussed the medicinal plants with antiepileptic effect focusing on active ingredients and their mode of action.

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Tolerability and Efficacy of Long-Term Medical Therapy in Primary Aldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.614 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A301-A302

Author(s):

Troy Puar ◽

Fengjie Tang ◽

Lih-Ming Loh ◽

Roger Foo ◽

Wann Jia Loh ◽

...

Keyword(s):

Side Effects ◽

Medical Therapy ◽

Primary Aldosteronism ◽

Male Gender ◽

Monitoring Strategy ◽

Biochemical Control ◽

Duration Of Treatment ◽

Limited Efficacy ◽

Dose Dependent

Abstract Introduction: Patients with primary aldosteronism (PA) have increased cardiovascular risk and studies have found that medical therapy fails to ameliorate this. This may be due to side effects and limited efficacy of medications at tolerable doses. Methods: We conducted a retrospective study on 201 patients with PA treated with medical therapy (spironolactone, eplerenone or amiloride) for PA from 2000–2020 at two tertiary centres. Patients were assessed for efficacy to achieve clinical and biochemical control, and for side effects. Results: 53.7% of patients achieved blood pressure <140/90mmHg, 44.6% achieved serum potassium ≥4.3mmol/L, and 63.2% achieved renin levels >1ng/ml/hr. Concordance between biochemical control as assessed by potassium and renin levels was 49%. 45.3% of patients experienced side effects, with 8.5% switching to another medication, 18.9% decreasing dose, and 10.0% stopping medications altogether. Risk factors for side effects were spironolactone use, dose ≥50mg, duration of treatment ≥1 year, male gender and unilateral PA. Patients with unilateral PA, compared to bilateral PA, used higher median doses of spironolactone, 75mg vs 50mg, P<0.001, but more had persistent hypokalemia, 20.5% versus 6.4%, P=0.007. 44 patients with unilateral PA underwent surgery after initial medical therapy, which further improved systolic and diastolic BP, from 142 to 134mmHg, P<0.001, and from 85 to 79mmHg, P<0.001, respectively. Conclusion: Dose-dependent side effects limit the efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. In patients with unilateral PA, surgery remains a better option compared to life-long medications.

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Toxicity of fipronil in rabbits as a therapeutic drug for "Psoroptes cuniculi": A preliminary observation

Journal of Experimental and Applied Animal Sciences ◽

10.20454/jeaas.2018.1399 ◽

2018 ◽

Vol 2 (3) ◽

pp. 260-265 ◽

Cited By ~ 1

Author(s):

Nagwa M. Elhawary ◽

Shimaa S.Gh. Sorour ◽

Eman K. Bazh ◽

Moshira A. El- Abasy ◽

Mostafa A. El-Madawy ◽

...

Keyword(s):

Body Weight ◽

Side Effects ◽

Adverse Effects ◽

Preliminary Observation ◽

Post Treatment ◽

Therapeutic Drug ◽

Psoroptes Cuniculi ◽

Limited Efficacy ◽

Current Report

In the current report, a preliminary observation to study the adverse effects of the broad use acaricides fipronil (FPN) in rabbits infested with Psoroptes cuniculi. Two separate groups (5 rabbits/each) treated topically (poured on at the base of the neck) with fipronil 5%, 1 vial/ 10 kilogram body weight (kg bw) and 1 vial/ 5 kg bw. After FPN spot on application, rabbits in both groups examined microscopically on the 7th, 14th, and 28th day post treatment and the number of live mites (larvae, nymphs, and adults) on each rabbit counted at the end of the experiment (28th day). The results showed that the number of mites in rabbits topically treated with FPN did not show significant decrease, moreover a decrease in both treated rabbits body weight (bw) and in performance observed clearly, with some attendant mortality. In conclusion, this work showed that FPN was with limited efficacy on P. cuniculi and had some undesirable side effects. Further and in-depth studies on FPN toxicity in rabbits and other animals are necessary.

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An approach to treatment modalities of keloids: a comparative study

International Journal of Research in Dermatology ◽

10.18203/issn.2455-4529.intjresdermatol20214911 ◽

2021 ◽

Vol 8 (1) ◽

pp. 45

Author(s):

Sweta S. Parmar ◽

Avani Modi

Keyword(s):

Side Effects ◽

Triamcinolone Acetonide ◽

Statistical Tests ◽

Treatment Modalities ◽

Complete Clearance ◽

Limited Efficacy ◽

Group 3 ◽

Group 2 ◽

Better Than ◽

Group 1

Background: In spite of the presence of such an array of treatment modalities, none of these can be claimed to be an ideal treatment option as most of them have limited efficacy, significant side effects or increased chances of recurrence. Hence the study was undertaken to search an ideal treatment for keloids which is safe, effective, and with low rate of recurrence.Methods: Total of 200 patients were recruited out of which only 160 patients were included in study. The patients were divided into three groups and administered with different modes of treatment. Patients in all the groups were followed up at 3 weekly intervals for evaluation of response. At the end of the study, the data was compiled and analysed using appropriate statistical tests.Results: In only 32 patients completed study in group 1, 2 and 3 respectively. Group 1, 2 and 3 were more or less equally efficacious with clearance rate. Complete clearance was seen in 24 patients in group 1 patients, in group 2 there were 22 patients with complete clearance and in group 3 there were 24 patients.Conclusions: Intralesional triamcinolone acetonide, intralesional triamcinolone acetonide with hyaluronidase and intralesional radiofrequency with intralesional triamcinolone acetonide are almost equally effective modalities for the treatment of keloids. But, intralesional triamcinolone acetonide with hyaluronidase fares better than other two as far as safety is concerned with least side effects.

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In VitroAntidiabetic Activity and Mechanism of Action ofBrachylaena elliptica(Thunb.) DC

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4170372 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Idowu Jonas Sagbo ◽

Maryna van de Venter ◽

Trevor Koekemoer ◽

Graeme Bradley

Keyword(s):

Side Effects ◽

Glucose Metabolism ◽

Mechanism Of Action ◽

Hepg2 Cells ◽

Protein Glycation ◽

Antidiabetic Activity ◽

No Production ◽

Triglyceride Accumulation ◽

Dpp Iv ◽

Alpha Glucosidase

In South Africa, the number of people suffering from diabetes is believed to be rising steadily and the current antidiabetic therapies are frequently reported to have adverse side effects. Ethnomedicinal plant use has shown promise for the development of cheaper, cost-effective antidiabetic agents with fewer side effects. The aim of this study was to investigate the antidiabetic activity and mechanism of action of aqueous leaf extract prepared fromBrachylaena elliptica. The potential of the extract for cytotoxicity was evaluated using MTT assay in HepG2 cells. The effects of the plant extract on glucose utilization in HepG2 cells and L6 myotubes, triglyceride accumulation in 3T3-L1, INS-1 proliferation, glucose metabolism in INS-1 cells, and NO production in RAW macrophages were also investigated using cell culture procedures. The inhibitory effects of the extract on the activities of different enzymes including alpha-amylase, alpha-glucosidase, pancreatic lipase, dipeptidyl peptidase IV (DPP-IV), collagenase, and CYP3A4 enzymes were evaluated. The extract also tested against protein glycation using standard published procedure. The plant extract displayed low level of toxicity, where both concentrations tested did not induce 50% cell death. The extract caused a significant increase in glucose uptake in HepG2 liver cells, with efficacy significantly higher than the positive control, berberine. The crude extract also displayed no significant effect on muscle glucose uptake, triglyceride accumulation in 3T3-L1, glucose metabolism in INS-1 cells, alpha-amylase, alpha-glucosidase, DPP-IV, lipase, protein glycation, and collagenase compared to the respective positive controls. The extract displayed a proliferative effect on INS-1 cells at 25μg/ml when compared to the negative control. The plant also produced a concentration-dependent reduction in NO production in RAW macrophages and also demonstrated weak significant inhibition on CYP3A4 activity. The findings provide evidence thatB. ellipticapossess antidiabetic activity and appear to exact its hypoglycemic effect independent of insulin.

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Tolerability and Efficacy of Long-term Medical Therapy in Primary Aldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab144 ◽

2021 ◽

Author(s):

Fengjie Tang ◽

Lih M Loh ◽

Roger S Foo ◽

Wann J Loh ◽

Dawn S T Lim ◽

...

Keyword(s):

Side Effects ◽

Medical Therapy ◽

Primary Aldosteronism ◽

Treatment Duration ◽

Male Gender ◽

Monitoring Strategy ◽

Biochemical Control ◽

Limited Efficacy ◽

Dose Dependent

Abstract Introduction Patients with primary aldosteronism (PA) have increased cardiovascular risk, and some studies find medical therapy less effective than surgery. This may be due to side effects and limited efficacy of medications at tolerable doses. Methods We conducted a retrospective study on 201 patients with PA treated with medical therapy (spironolactone, eplerenone or amiloride) for PA from 2000-2020 at two tertiary centres. Patients were assessed for efficacy to achieve clinical and biochemical control, and for side effects. Results Amongst 155 patients on long-term medications, 57.4% achieved blood pressure <140/90mmHg, 90.1% achieved normokalemia(48.0% achieved potassium≥4.3mmol/L), and 63.2% achieved renin>1ng/ml/hr. Concordance of biochemical control using potassium and renin levels was 49.1%. 52.3% of patients experienced side effects, with 10.3% switching to another medication, 22.6% decreasing dose, and 11.0% stopping medications. Risk factors for side effects were spironolactone use, dose≥50mg, treatment duration ≥1year, male gender and unilateral PA. Patients with unilateral PA, compared to bilateral PA, used higher spironolactone doses, 57mg vs 50mg, P<0.001, and had more side effects, 63.2% versus 41.8%, P=0.008. Amongst 46 patients with unilateral PA who underwent surgery after initial medical therapy, surgery further improved systolic and diastolic BP, from 141 to 135mmHg, P=0.045, and from 85 to 79mmHg, P=0.002, respectively. Conclusion Dose-dependent side effects limit the efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. For unilateral PA, surgery remains preferable to medications, as surgery leads to better control with less long-term side-effects.

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