Table 2 - uploaded by Alejandro Arenas-Pinto
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To describe the clinical, epidemiological, and biochemical characteristics of published cases of lactic acidosis (LA) and to generate hypotheses concerning risk factors associated with this complication.
Systematic review of cases reported in the medical literature.
217 published cases were identified, 90 of which fulfilled the study definition and...
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A mitochondrial defect was investigated in an infant with fatal congenital lactic acidosis (3-14 mM), high lactate-to-pyruvate ratio, hypotonia, and cardiomyopathy. His sister had died with a similar disorder. Resting oxygen consumption was 150% of controls. Pathological findings included increased numbers of skeletal muscle mitochondria (many with...
Lactic acidosis is the result of imbalance between the systemic formation of lactate and its hepatic metabolism. In cancer patients, lactic acidosis is mainly associated with hematologic malignancies (leukemia and lymphomas) and the mechanism is known as Warburg's effect. We report a 76-year-old male known to have hypertension and coronary artery d...
The effects of hyperglycemia on the time course of changes in cerebral energy metabolite concentrations and intracellular pH were measured by nuclear magnetic resonance (NMR) spectroscopy in rats subjected to temporary complete brain ischemia. Interleaved 31P and 1H NMR spectra were obtained every 5 min before, during, and for 2 h after a 30-min bi...
Citations
... On the other hand, this therapy promoted health complications by increasing the risk of functional decline and causing changes in body composition such as lipodystrophy (Fiorenza et al., 2011;Cardoso et al., 2013;Richert et al., 2014;Montoya et al., 2019), all of which have a negative relationship with certain components of physical fitness related to health. Other damage described in the literature report on the increase in metabolic acidosis and oxidative stress induced by the pro-inflammatory cytokines expressed by HIV that compromise airway permeability or damage lung tissues, that is, there is impairment of cardiac function (Arenas-Pinto et al., 2003;Blas-Garcia et al., 2011;Capili et al., 2011). ...
The aim of the study was to evaluate the effect of training and detraining on the physical fitness components of people living with HIV/AIDS (PLHA). The study was characterized as experimental with a sample composed of 21 people divided into two groups: 11 volunteers (PLHA, 46.9 ± 8.0 years, 63.8 ± 12.7 kg, 161.7 ± 8.7 cm, 7 men, and 4 women), using antiretroviral therapy (ART) and 10 people without HIV/AIDS in the control group (CG, 43.8 ± 13.8 years, 75.2 ± 11.2 kg, 163.3 ± 7.8 cm, 3 men, and 7 women), with the same average age and level of physical activity. The intervention, applied to both groups, consisted of combined training for 15 weeks, followed by detraining for 5 weeks. Before and after the training and detraining period the following parameters were evaluated: body composition by dual energy radiological absorptiometry (DXA), cardiorespiratory fitness by ergospirometer, and strength of upper and lower limbs by isometric dynamometer. The results show the effect of the intervention moments on the strength and oxygen consumption variables (time factor), considering the two study groups. Regarding the analysis of the interaction (group vs. time), there was a significant effect on the isometric extension strength of the left (p = 0.019) and right (p = 0.030) knees, with training (left: 10.4%; right: 12.4%) and detraining (left: −10.8%; right: −12.1%) effect in PLHA, when compared with the control group (left: 8.1 and 3.9%, respectively; right: 11.5 and −0.2%, respectively). In addition, there was a significant interaction on ventilatory threshold 1 (p = 0.002), indicating a significantly greater increase with training (27.3%) and decrease with detraining (−22.7%) in the PLHA group compared with the Control group (19.9 and −6.7%, respectively). In conclusion, combined training and the subsequent period of detraining caused similar responses in body composition, isometric strength, and cardiorespiratory fitness of PLHA and CG, except for the extensor strength of the lower limbs and ventilatory threshold 1, which presented positive effects on training and negative effects on detraining for PLHA.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03075332.
... The mechanism underlying this condition is mediated by mitochondrial toxicity. Renal involvement manifests with acute renal failure, primarily due to prerenal causes (hypovolemia, reduced renal perfusion) [110]. ...
Antiretroviral therapy (ART) has significantly improved life expectancy of infected subjects, generating a new epidemiological setting of people aging withHuman Immunodeficiency Virus (HIV). People living with HIV (PLWH), having longer life expectancy, now face several age-related conditions as well as side effects of long-term exposure of ART. Chronic kidney disease (CKD) is a common comorbidity in this population. CKD is a relentlessly progressive disease that may evolve toward end-stage renal disease (ESRD) and significantly affect quality of life and risk of death. Herein, we review current understanding of renal involvement in PLWH, mechanisms and risk factors for CKD as well as strategies for early recognition of renal dysfunction and best care of CKD.
... [12][13][14][15] Although systematic reviews for medication-induced lactate level elevations exist for single agents or classes of agents, to our knowledge, no comprehensive systematic review exists. 16,17 The purpose of this systematic review is to identify published reports of medication-induced hyperlactatemia and lactic acidosis to aid clinicians in diagnosing and comprehending the underlying mechanism of this rare adverse drug effect, and to provide management strategies. ...
... Meta-Analysis of Individual Participant Data (PRISMA-IPD) recommendations for reporting and was registered on PROSPERO (unique identification number CRD42017072920), the international prospective register of systematic reviews. 17 ...
... Hyperlactatemia was defined as a lactate level ≥ 2 mmoL/L with a pH ≥ 7.35, and lactic acidosis was defined as a lactate level ≥ 2 mmoL/L with either a pH < 7.35 or a bicarbonate level < 20 mmol/L. 2 Metformin-and NRTI-related causes of hyperlactatemia were excluded since they have been described in literature. 16,17 The following data were extracted from the included articles: medication name, dose, route, Figure 3. ...
Hyperlactatemia and lactic acidosis are two syndromes that are associated with morbidity and mortality. Medication‐induced hyperlactatemia and lactic acidosis are diagnoses of exclusion and have the potential to be overlooked. The purpose of this systematic review is to identify published reports of medication‐induced lactate level elevations to aid clinicians in diagnosing and comprehending the underlying mechanism of this rare adverse drug effect, and to provide management strategies. The PubMed database was searched for case reports, case series, retrospective studies, and prospective studies describing cases of medication‐induced lactate level elevation, including lactic acidosis and hyperlactatemia, published between January 1950 and June 2017. A standardized search strategy was used, and the articles identified underwent two rounds of independent evaluation by two reviewers to assess for inclusion. Articles were included if they described at least one patient older than 12 years of age with hyperlactatemia or lactic acidosis caused by a medication with United States Food and Drug Administration (FDA) approval and if alternative etiologies for an elevated lactate level were ruled out. Metformin and nucleoside/nucleotide reverse transcriptase inhibitors were excluded since the pathophysiology and incidence of lactic acidosis have been well established for these agents. Overall, 1918 articles were identified, and 101 met inclusion criteria. A total of 286 patients experienced medication‐induced lactate level elevations, from which 59 unique medications were identified. The most commonly identified agents were epinephrine and albuterol. Medication‐induced lactate level elevation was classified as lactic acidosis (64.0%), hyperlactatemia (31.1%), or not specified (4.9%). The doses ingested included FDA‐labeled doses (86%), intentional overdoses (10.8%), or prescribed doses exceeding the FDA‐labeled dose (3.1%). Medications were continued without a change (40.8%), were permanently discontinued (34.4%), were continued with a dosage reduction (11.6%), or were initially withheld then resumed after lactate level normalized (2.9%); medication management for the remaining 10.0% was not reported. Forty‐six patients died (16%). Six deaths were attributed by treating clinicians to be secondary to medication‐induced lactic acidosis. Management strategies were heterogeneous, and treatment included supportive care, exogenous bicarbonate therapy, medication specific antidotes, and decontamination strategies. Unexplained lactate level elevations should prompt clinicians to assess for medication‐induced lactate level elevations. Pharmacists are members of the health care team that are well positioned to serve as experts in the diagnosis and management of medication‐induced lactate level elevations. This article is protected by copyright. All rights reserved.
... Duration of exposure to D-drugs was calculated as a cumulative exposure (calculated by area under the curve) to the specified NRTIs. These antiretrovirals inhibit gamma-DNA polymerase, the enzyme responsible for mitochondrial DNA replication, and thus are associated with mitochondrial DNA depletion and mutation, which ultimately results in dysfunctional cellular respiration [64][65][66]. In addition, these agents may induce oxidative stress and deplete L-carnitine in the skeletal muscle [67,68]. ...
... In addition, these agents may induce oxidative stress and deplete L-carnitine in the skeletal muscle [67,68]. Mitochondrial damage associated with D-drug exposure may lead to notable clinical manifestations including muscle dysfunction and exercise intolerance [65]. Of note, at the point of recruitment, 31% were currently receiving D-drugs whereas 73% had a previous exposure. ...
Objectives:
In a clinic-based, treated HIV-infected cohort, we identified individuals with sarcopenia and compared with age, sex and ethnically matched controls; and investigated associated risk factors and health outcomes.
Design:
Sarcopenia (age-related muscle loss) causes significant morbidity to the elderly, leading to frequent hospitalizations, disability and death. Few have characterized sarcopenia in the HIV-infected who experience accelerated aging.
Methods:
Sarcopenia was defined as low muscle mass with weak grip strength and/or slow gait speed using lower 20th percentiles of controls. Multivariate logistic and linear regression analyses were used to explore risk factors and health-related outcomes associated with sarcopenia among HIV-infected individuals.
Results:
We recruited 315 HIV-infected individuals aged at least 25 years with at least 1-year history of undetectable viral load on treatment (HIV RNA <50 copies/ml). Percentage of sarcopenia in 315 HIV-infected was 8%. Subsequently, 153 of the 315 were paired with age, sex and ethnically matched HIV-uninfected. The percentage of sarcopenia in the HIV-infected (n = 153) compared with uninfected (n = 153) were 10 vs. 6% (P = 0.193) respectively, whereas of those at least 50 years of age among them were 17% vs. 4% (P = 0.049), respectively. Associated risk factors among the HIV-infected include education level, employment status, BMI, baseline CD4 count, duration on NRTIs and GGT levels. Identified negative outcomes include mortality risk scores [5.42; 95% CI 1.46-9.37; P = 0.007) and functional disability (3.95; 95% CI 1.57-9.97; P = 0.004).
Conclusion:
Sarcopenia is more prevalent in HIV-infected at least 50 years old compared with matched controls. Our findings highlight associations between sarcopenia with loss of independence and greater healthcare burden among treated HIV-infected individuals necessitating early recognition and intervention.
... It is a subtype of metabolic acidosis, where excessive acid is due to a problem with the body's metabolism. Apart from other causes, stavudine can influence the accumulation of lactate [47]. A study conducted by Gerard et al. [48] reported that the incidence of lactic acidosis was higher in the patients treated with stavudine based regimens compared to non-stavudine based regimens. ...
... Literature reports from developed countries suggest an incidence rate for SHL of 5 -10/1 000 patients per year on NRTIs and 1/1 000 patients per year for the very severe form (LA), which is associated with a high expected mortality. [8] In South Africa (SA), SHL/LA incidence appears notably high, [9][10][11][12][13][14][15] especially in KwaZulu-Natal (KZN) Province, which is predominantly inhabited by the SA Zulu-speaking population. [10,12,14] The objective of this study was to detect if known mutations in mtDNA polymerase-γ (POLG1) [16,17] reported to be associated with mitochondrial toxicity are also linked with NRTI-induced SHL/LA in the SA Zulu-speaking population. ...
... clearly demonstrates that the use of stavudine poses a risk in the development of SHL/LA, as documented by other investigators. [8,9,11,12,14,21] While a significant number of the cases (42/59) were on zidovudine treatment at the time of enrolment in the study, only one patient among the control group (n=57) was on similar treatment. The 42 cases on zidovudine did not show any symptoms or relapse of SHL/LA, ...
... These risk factors are consistent with those reported by other studies in related settings, [10,12,14] as well as in other studies globally. [8,15,[24][25][26] In this study, the baseline age of the cases and controls was significantly different (p=0.015), with a median age of 38 (IQR 33 -45) and 33 (IQR 28 -40) years for cases and controls, respectively. This is in good agreement with studies that have shown associations between SHL/ LA and advanced age. ...
Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to theuse of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA.
Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy.
Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the
R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results.
Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males.
Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.
... Literature reports from developed countries suggest an incidence rate for SHL of 5 -10/1 000 patients per year on NRTIs and 1/1 000 patients per year for the very severe form (LA), which is associated with a high expected mortality. [8] In South Africa (SA), SHL/LA incidence appears notably high, [9][10][11][12][13][14][15] especially in KwaZulu-Natal (KZN) Province, which is predominantly inhabited by the SA Zulu-speaking population. [10,12,14] The objective of this study was to detect if known mutations in mtDNA polymerase-γ (POLG1) [16,17] reported to be associated with mitochondrial toxicity are also linked with NRTI-induced SHL/LA in the SA Zulu-speaking population. ...
... clearly demonstrates that the use of stavudine poses a risk in the development of SHL/LA, as documented by other investigators. [8,9,11,12,14,21] While a significant number of the cases (42/59) were on zidovudine treatment at the time of enrolment in the study, only one patient among the control group (n=57) was on similar treatment. The 42 cases on zidovudine did not show any symptoms or relapse of SHL/LA, ...
... These risk factors are consistent with those reported by other studies in related settings, [10,12,14] as well as in other studies globally. [8,15,[24][25][26] In this study, the baseline age of the cases and controls was significantly different (p=0.015), with a median age of 38 (IQR 33 -45) and 33 (IQR 28 -40) years for cases and controls, respectively. This is in good agreement with studies that have shown associations between SHL/ LA and advanced age. ...
Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA.
Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy.
Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results.
Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males.
Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.
... Literature reports from developed countries suggest an incidence rate for SHL of 5 -10/1 000 patients per year on NRTIs and 1/1 000 patients per year for the very severe form (LA), which is associated with a high expected mortality. [8] In South Africa (SA), SHL/LA incidence appears notably high, [9][10][11][12][13][14][15] especially in KwaZulu-Natal (KZN) Province, which is predominantly inhabited by the SA Zulu-speaking population. [10,12,14] The objective of this study was to detect if known mutations in mtDNA polymerase-γ (POLG1) [16,17] reported to be associated with mitochondrial toxicity are also linked with NRTI-induced SHL/LA in the SA Zulu-speaking population. ...
... clearly demonstrates that the use of stavudine poses a risk in the development of SHL/LA, as documented by other investigators. [8,9,11,12,14,21] While a significant number of the cases (42/59) were on zidovudine treatment at the time of enrolment in the study, only one patient among the control group (n=57) was on similar treatment. The 42 cases on zidovudine did not show any symptoms or relapse of SHL/LA, ...
... These risk factors are consistent with those reported by other studies in related settings, [10,12,14] as well as in other studies globally. [8,15,[24][25][26] In this study, the baseline age of the cases and controls was significantly different (p=0.015), with a median age of 38 (IQR 33 -45) and 33 (IQR 28 -40) years for cases and controls, respectively. This is in good agreement with studies that have shown associations between SHL/ LA and advanced age. ...
Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA.
Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy.
Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results.
Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males.
Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.
... Regarding lactic acidosis, NRTIs are known to inhibit mitochondrial DNA synthesis and induce mitochondrial disorders and lactic acidosis (16). In our patient, marked lactic acidosis was observed at the onset of NOMI, but it rapidly resolved after resection of the ischemic intestine. ...
An elderly woman with human immunodeficiency virus-1 infection developed short bowel syndrome as a result of extensive intestinal resection. Considering the possibility of poor absorption of antiretroviral drugs (ARVs), therapeutic drug monitoring (TDM) was performed. A single-dose test of 6 ARVs (darunavir, ritonavir, lopinavir, etravirine, maraviroc, and raltegravir) did not provide information on the appropriate ARV, and repeated TDM under continuous antiretroviral therapy resulted in viral suppression below 50 copies/mL, which was considered to be treatment success. These assessments suggest the importance of TDM in the steady state for the successful treatment of individuals with impaired gastrointestinal function using ARVs.
... These are the binding sites for the P4, P3, P2, P1, P1 , P2 , P3 , and P4 residues of an octapeptide substrate counted from the bond, which is cleaved during hydrolysis, called the "scissile" bond [21]. Side effects of HIV-1 inhibitors such as drug intolerance and drug toxicity are significant problems for all drugs used to treat HIV and accordingly some kinds of modifications are needed [24][25][26][27][28][29]. The side effects and the clinical emergence of resistant mutants in HIV-1 mean that new protease inhibitors need to be developed. ...
The molecular modeling studies include quantitative structure activity relationship, IR spectra, and docking calculations, occurring for novel inhibitors based on chitosan dimer which were tried as HIV protease. The inhibitors were investigated with molecular modeling calculations at different level of theories. Each compound has phenol with hydroxymethylcarbonyl (HMC) group which added to chitosan in positions 2, 3, 2′, or 3′. The geometry of studied compounds is optimized with semiempirical PM3 method. Quantitative structure activity relationship (QSAR) properties of the suggested compounds are calculated at the same level of theory. Depending on QSAR calculations, the compounds with positions 2 and 2′ are less hydrophilic. The position 2′ compound makes good docking interaction into HIV protease active site. Calculated IR spectra indicate that the interaction through hydrogen bonding through the hydrogen of OH at positions 3 and 3′ gives rise to two OH bands one for chitosan and the other for phenol and HMC group. While at position 3′ CH band starts to appear.
