Experimental Gentamicin Nephrotoxicity and Agents that Modify it: A Mini-Review of Recent Research

Authors


Author for correspondence: Badreldin H. Ali, Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos University, PO Box 35, Postal code 123, Sultanate of Oman, Al Khod, Oman (fax +968 2441 3419, e-mail alibadreldin@hotmail.com; akthmali@squ.edu.om).

Abstract

Abstract:  The aminoglycoside antibiotic gentamicin (GM) is still widely used against infections by Gram-positive and Gram-negative aerobic bacteria. Its therapeutic efficacy, however, is limited by renal impairment that occurs in up to 30% of treated patients. The drug may accumulate in epithelial tubular cells causing a range of effects starting with loss of the brush border in epithelial cells and ending in overt tubular necrosis, activation of apoptosis and massive proteolysis. GM also causes cell death by generation of free radicals, phospholipidosis, extracellular calcium-sensing receptor stimulation and energetic catastrophe, reduced renal blood flow and inflammation. Many drugs have been shown to either ameliorate or potentiate GM nephrotoxicity. This article aims at updating the literature that has been published in the past decade on the effects of agents that either ameliorate or augment the nephrotoxicity of this aminoglycoside. Notable among the new ameliorating procedures are gene therapy, such as intravenous cell therapy with serum amyloid A protein-programmed cells, and the use of some novel antioxidant agents and oils of natural origin. These include, for example, green tea, garlic saffron, grape seed extracts as well as sesame and oleanolic oils. Agents that may augment GM nephrotoxicity include indomethacin, cyclosporin, uric acid and the Ca++-channel blocker verapamil. Most of the nephroprotective agents mentioned here have not been tested in large controlled clinical trials. Because of their relative safety and effectiveness, antioxidant agents seem to be good candidates for testing in humans.

The aminoglycoside antibiotics are used, either alone or in combination with cell wall-active agents, for the treatment of severe/life-threatening infections caused by Gram-positive and Gram-negative aerobes [1]. Gentamicin (GM) is probably the most commonly used and studied of all the aminoglycosides [2]. One serious limitation to the use of this antibiotic is that it can cause ototoxicity and nephrotoxicity, and, in some situations, these side effects are so severe that the use of the drug must be discontinued. It has been estimated that up to 30% of patients treated with GM for more than 7 days show some signs of renal impairment [3]. GM nephrotoxicity has been investigated in several experimental models in rabbits, mice and rats [4–6], and several strategies and agents have been used, with various degrees of success, in an attempt to protect or reverse renal GM damage [3,7,8]. This would be expected to have important clinical implications in increasing the safety of the drug. Because the pharmaceutical industry, in general, is not investing adequately in the development of new antibiotics, and antimicrobial resistance is on the increase, revival of older antibiotics for use might be a viable option.

Some reviews have been published recently on specific aspects of GM nephrotoxicity. For example, Zorov [9] wrote about the role of renal mitochondria on protection against GM nephrotoxicity. Koyner et al. [8] reviewed the role of antioxidants in either preventing or mitigating GM nephrotoxicity, while Martínez-Salgado et al. [10] and Servais et al. [11] reported on the latest information about the cellular and molecular mechanisms of GM nephrotoxicity. A more recent review deals with the integrative glomerular and tubular effects and their possible interplay [12]. Another recent review describes the possible therapeutic approaches to blunt the GM-induced nephrotoxicity [2] and includes a simplified diagram describing the mode of action of antioxidants (and other agents) on the nephrotoxicity.

Our current review updates a previously published one [3] by including papers that have appeared during the past decade and that have dealt with either the amelioration or augmentation of experimental GM nephrotoxicity. It was noted that most of the advances in the area of GM nephrotoxicity in the past decade were centred on the molecular biology and genetic basis of the mechanisms of the nephrotoxicity and its pathophysiology rather than on novel agents that could be utilised to ameliorate the toxicity [12–14].

Agents that either ameliorate or prevent GM nephrotoxicity

Extracts of medicinal plants.

Several extracts of medicinal plants have been tested against GM-induced nephrotoxicity in rats (table 1). The basis of the protective action of these plant extracts is not known with certainty, but it was thought to be because of their antioxidant properties. As reviewed by Koyner et al. [8], generation of reactive oxygen metabolite (ROM) may be the basis of a variety of insults, such as GM nephrotoxicity, and treatment with several natural and synthetic antioxidant substances has been shown to be useful in either its prevention or amelioration in experimental rats. The following is a brief description of some selected medicinal plants extracts.

Table 1. 
Partial list of some natural antioxidant agents that have been used against gentamicin (GM)- induced nephrotoxicity.
AgentDose of antioxidantGM (mg/kg)EffectsReference
S-allylcystine (from garlic)250 mg/kg, 24 hr before the first dose of GM, i.p. 125 mg/kg, every 12 hr, 4 days, i.p.70, every 12 hr, 4 days, s.c.Protection against biochemical signs of GM nephrotoxicity73
Diallyl sulphide50 mg/kg/day for 4 days, intragastrically125/24 hr/4 days and 125/24 hrProtect and decrease oxidative stress in renal cortex15
Gum arabic2 ml/kg of 10% w/v, 10 days, p.o.80, last 6 days of the treatment, i.m.Modest amelioration in some of the histological and biochemical signs of GM nephrotoxicity74
Pongamia pinnata flowers300 and 600 oral mg/kg, 10 days40, 5 days, i.m.Mitigate biochemical, functional and histological signs of GM nephrotoxicity75
Nigella sativa oil0.5,1, or 2 ml/kg day for 10 days80, last 6 days of treatmentAmeliorating signs of GM nephrotoxicity in rats23
Hemidesmus indicus5 g/kg single dose, p.o.90, last 6 days of treatmentReduced renal impairment, induced by GM in rats76
Curcumin (from turmeric)200 mg/kg, 10 days, p.o.80, last 6 days of treatmentAmelioration of biochemical and histological signs of GM nephrotoxicity77
PESB (phenolic extract of soybean)1000 mg/kg/day for 12 days p.o.80, 12 days s.c.Amelioration of nephrotoxicity because of action of the antioxidant polyphenolic content of the soyabean78
Thymoquinone50 mg/l in drinking water for 4 days80, 8 days, i.pPrevents nephrotoxicity; decreases oxidative stress and preserves the activity of antioxidant enzymes24
Bauhinia purpurea300 mg/kg, 8 days, p.o100, 8 days, i.pProtection against biochemical and histological signs of GM nephrotoxicity79
Phyllanthus amarus(100–400) mg/kg, single oral 1 hr before the dose of GM, 14 days40, 14 days, i.pProtection against biochemical and histological signs of GM nephrotoxicity80
Green tea extract95 mg/g (3%), 25 days, p.o80, 25 days, i.pProtection and amelioration of the oxidative stress nephrotoxicity81
Nigella sativa0.2 or 0.4 ml/kg, 1 hr before the injection of GM, 6 days, i.p100, 6 days, i.pProtection against biochemical and histological signs of GM nephrotoxicity25
Green tea300 mg/kg/d, p.o80, i.pProtection against biochemical and histological signs of GM nephrotoxicity82
Sida rhomboidea(200 and 400) mg/kg, 8 days, p.o.100, 8 days, i.pAmelioration of the oxidative stress and protection against biochemical signs of GM nephrotoxicity83

Compounds from aged garlic.

Aged garlic extract, garlic powder and the compounds isolated from them, namely S-allylcysteine, diallyl sulphide and diallyl disulphide, have been reported to mitigate GM-induced nephrotoxicity in rats [15,16]. This beneficial action was also shown not to interfere with the in vitro activity of the antibiotic in cultures of Escherichia coli [17]. Additionally, S-allylcysteine, diallyl sulphide and diallyl disulphide alone were found to have a bacteriostatic action against E. coli and to enhance the antibacterial action of GM. The mechanism of the ameliorative action of these compounds is associated with their reported action as strong antioxidants [18], and their additive/potentiating action on the antibacterial effect of GM can be ascribed to their well-known antibacterial action [18].

Withania somnifera.  Jeyanthi and Subramanian [19] reported that treatment with Withania somnifera root, an indigenous medicinal herb commonly used in the ancient ayurvedic traditional medicine, and known to have a strong antioxidant activity, can protect rats against GM nephrotoxicity. The root extract, given for two weeks, at an oral dose of 500 mg/kg (and to a lesser extent at doses of 250 and 750 mg/kg) significantly reversed the physiological, biochemical and histological changes induced by GM (100 mg/kg for 10 days). This nephroprotective action was confirmed by the same authors, who further found that treatment with the extract enhanced the oxidant status in the rats, probably because of the presence of flavonoids and several other bioactive compounds in the extract [20].

Saffron (Crocus sativus) is used medicinally for a number of different diseases and conditions (reviewed by Rios et al. [21]). The aqueous extract of the plant has been shown to reverse renal ischaemia reperfusion-induced oxidative injury [22]. When saffron (40 and 80 mg/kg/day for 10 days) was given by the oral route concomitantly with GM (100 mg/kg/day for 10 days, IP), the plant was effective in significantly and dose-dependently mitigating some standard biochemical and histological changes induced by GM in the kidneys and plasma. The antioxidant compounds in the saffron (mainly crocetin) have been postulated to be responsible for the nephroprotective action.

Nigella sativa extract, oil and its active ingredient, thymoquinone, have been tested by several researchers [23–25] who have all confirmed their mitigating effect against GM nephrotoxicity in rats and ascribed this to the antioxidant action of either the plant extract or oil, and also possibly to the antagonism of the extract or oil to the adverse action of GM on phospholipids of the proximal tubules. Ali [23] was the first to report that N. sativa oil (0.5, 1.0 or 2.0 ml/kg/day for 10 days) ameliorated the nephrotoxicity of GM (80 mg/kg/day IM, and concomitantly with the oil during the last 6 days of treatment), and the histological and biochemical indices of nephrotoxicity of GM (including indices of oxidative stress). Thymoquinone (50 mg/l in drinking water) for 8 consecutive days was also found to be effective in significantly reducing, and in some instances completely reversing, the histological and biochemical indices of GM nephrotoxicity [24]. This was ascribed to the ability of thymoquinone to mitigate oxidative stress, preserve the integrity of the oxidative enzymes and also possibly prevent the energy decline in kidney tissues.

Seseme oil (Sesamum indicum).

The effect of seseme oil on the nephrotoxicity of GM has recently been investigated by Hsu et al. [26] and Periasamy et al. [27]. Using several biochemical, histological, molecular biological and immunohistochemical methods, a single dose of sesame oil (1, 2 or 4 ml/kg) has been shown to protect, dose-dependently, against nephrotoxicity induced by subcutaneous GM injection (100 mg/kg/day for 7 days) when given 24 hr after the last dose [27]. Researchers from the same laboratory [26] tested graded doses of sesame oil (0.25, 0.5 or 1 ml/kg) on the nephrotoxicity induced by a single dose of GM (100 mg/kg). Using the above used parameters, the authors reported that sesame oil was effective in significantly ameliorating GM-induced renal injury and lipid peroxidation, as well as the production of hydroxyl radicals, superoxide anions and NO. It was also reported that sesame oil inhibited xanthine oxidase activity and inducible NOS in GM-treated rats, supporting the view that the purported nephroprotective effect of sesame oil was mediated via inhibition of the GM-induced oxidative stress. Previously, the same group reported a nephroprotective effect against endotoxin-induced renal failure in rats [28].

Eugenol, a phenolic antioxidant from, for example, the plant Eugenia aromaticum, at an intramuscular dose of 100 mg/kg/day for 10 days, has been shown to ameliorate some physiological, biochemical and histological indices of GM nephrotoxicity in rats when given at an IP dose of 100 mg/kg/day for 6 days [29].

Spirulina, a cyanobacterial genus (blue-green algae), is a medicinal food that has been used in the Indian subcontinent and elsewhere for many centuries and is reported to be endowed with strong anti-inflammatory, antioxidant and hypolipidaemic activities (reviewed by Deng and Chow [30]). Spirulina fusiformis was given orally at doses of 0.5, 1.0 or 1.5 g/kg, 2 days before, and 8 days concomitantly with GM (100 mg/kg). The treatment ameliorated the GM-induced histopathological and biochemical indices of acute renal failure (ARF), significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, SOD and catalase [31]. Karadeniz et al. [32] reported that oral administration of S. platensis (1 g/kg/day for 7 days) given concomitantly with intraperitoneal GM (100 mg/kg/day for 7 days) was effective in protecting against the renal histopathological and biochemical changes (including the generation of free radicals) induced by GM alone. Similar findings were reported by Avdagic et al. [33] using similar doses of S. platensis and GM, except that the treatment was carried out for 9 days. The three papers suggested that the basis of the nephroprotective action of Spirulina was its antioxidant activity against the generation of free radicals induced by GM.

Antioxidant vitamins (C and E).

As GM nephrotoxicity was shown by several workers to involve generation of free radicals [3,7,8], it was logical that antioxidants could be effective in preventing or, at least, ameliorating the nephrotoxicity. Vitamin C (ascorbic acid, AA) and vitamin E (tocopherols) are known antioxidant agents that have been used by many researchers, either alone or in combination to reverse the nephrotoxic actions of GM (for example, Ben–Ismail et al. [34]; Kadkhodaee et al. [35,36]). In the paper of Kadkhodaee et al. [35], an in situ model of isolated kidney was used in which GM (200 μg/ml) was added to the perfusate. To one group, AA was given in the drinking water (200 mg/l) to the rats for 3 days, and the perfusate (100 mg/l), and to another group, as for the AA group, but with vitamin E (100 mg/rat) injected intramuscularly 12 hr before the start of the experiment. In another group, AA and vitamin E were given together. The results of this work confirmed that coadministration of moderate doses of AA and vitamin E protects against GM nephrotoxicity. A subsequent paper by the same authors and using the same methodology confirmed that vitamin E, either alone or in combination with AA, was effective in preserving the activity of superoxide dismutase (SOD) in GM-treated rats [36].

Gene therapy.

Gene therapy with interactive cytokines and growth factors is a relatively new approach to treat and prevent many diseases and conditions, including ARF [37]. The basis of these therapies is their ability to expand specific cells in tissue culture to carry out differentiated tasks and then to inject these cells into the affected subject using different methods and as drug delivery vehicles of a single protein or to perform physiological functions. One of these novel strategies is the injecting of serum amyloid A protein (SAA), which is known to be a prominent component of the acute-phase response that is strongly expressed in developing and repairing kidneys and which promotes tubulogenesis [38]. Kelly et al. [4] reprogrammed relatively undifferentiated NRK52Ecells with the mouse SAA1.1 gene and transplanted SAA-positive and -negative cells into rats with GM-induced ARF (and two other models of ARF). SAA-positive cells were reported to accelerate renal recovery, and within 2 days, there was a significant improvement in the signs of the ARF, consistent with an early paracrine effect. This was considered to be a possible powerful and novel treatment of ARF.

Nitric oxide (NO).

The gaseous radical NO is important in several physiological and pathophysiological events in many body systems, such as cellular signalling, cellular energetics, host defence and inflammation [39] and is involved in the pathophysiology of ARF [40]. The role played by NO in nephrotoxicity is thought by some as controversial, although some workers have reported that it increased renal injury through its reactions with a superoxide radical and generation of a cytotoxic peroxynitrite [41].

Among other factors, the potent vasodilator NO has been implicated in the pathophysiology of GM nephrotoxicity, being a potent regulator of systemic and intrarenal haemodynamics and renal tubular function [41]. Rats treated with GM (100 mg/kg/day for 10 days) exhibited the expected decrease in renal function and also had increased NO in plasma and a concomitant decrease in urine. This probably occurred to counterbalance the effects of vasoconstrictor agents such as angiotensin and/or prostaglandins, or it was a reaction against the vasoconstrictor action of GM, or the generation of free radicals (such as peroxynitrite). In the renal tissues of the GM-treated rats, inducible nitric oxide synthase (iNOS) was not expressed by either RT-PCR or Western blot analysis [41].

NO is produced by NOS, of which there are three isoforms (endothelial eNOS, neuronal nNOS and inducible iNOS). The last is known to aggravate renal failure, and its selective inhibition would be expected to ameliorate signs of GM nephrotoxicity. Intravenous administration of the selective iNOS inhibitor, N-imino-ethyl lysine (L-NIL), together with GM significantly ameliorated biochemical and renal histological indices caused by GM. However, others have shown that intravenous administration of a NOS inhibitor (L-NIL), together with GM, produced the opposite effect [42]. These results were in line with those previously reported for GM-induced nephrotoxicity using different routes for drug administration (viz, giving L-arginine, the substrate of NO, in the drinking water and L-NAME) [43].

Dihydropyridine calcium channel blockers.

It has been reported by Berkeles et al. [44] that dihydropyridine calcium channel antagonists of the first, second and third generations (such as nifedipine, nitrendipine and amlodipine, respectively) possess antioxidant activity and can reduce the generation of reactive oxygen species (ROS), independently of their action on calcium channels. More recently, Li et al. [45], using various physiological, biochemical, histopathological and histoimmunochemical parameters, showed that dihydropyridine calcium channel blockers have differential actions to induce nephrotoxicity in rats injected intraperitoneally with GM at a dose of 100 mg/kg/day for 7 days. Nifedipine (15 mg/kg/day for 7 days) and amlodipine (5 mg/kg/day for 7 days) were effective in ameliorating the studied signs of nephrotoxicity, while nitrendipine (10 mg/kg/day for 7 days) either had no effect or actually worsened the signs. The beneficial action of the dihydropyridine calcium channel blockers on GM-induced nephrotoxicity has been ascribed to a possible donation of electrons to the propagating radicals to reduce them to a non-reactive species, and that the intrinsic structural characteristics of the dihydropyridine calcium blockers are essential in determining their antioxidant potential [44,45]. Although Li et al. [45] did not specifically discuss the failure of nitredipine to antagonise the nephrotoxicity of GM, the latter factor may explain the contrasting effects of some of these calcium channel blockers. In addition, amlodipine has been reported to have a beneficial haemodynamic action in patients treated with gentamicin, possibly because of its vasodilatory action that leads to an increase in glomerular filtration rate [46]. It is possible that this action was also involved in mitigating GM nephrotoxicity in rats.

Other drugs

Metformin.

The anti-diabetic drug metformin can induce apoptosis in pancreatic cancer cells [47], and it has also been reported to diminish oxidative stress [48] and apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction [49]. In the last work [49], it was found that oral metformin treatment (100 mg/kg/day for 13 days) was effective in protecting against ARF induced by intraperitoneal treatment with GM (150 mg/kg). This was accompanied by diminished lipid peroxidation, increased antioxidant systems and an improved renal histological picture. GM is thought of now as a mitochondrial toxin [9]. In vitro, it has also been reported that metformin significantly antagonised the GM-induced depletion in respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. Based on the above in vivo and in vitro results, it was concluded that pleiotropic effects of metformin ameliorate GM-induced ARF and improve mitochondrial homoeostasis. Metformin has the potential to become a clinically useful nephroprotection agent, as it appears to be both effective and safe [50].

The action of metformin on GM nephrotoxicity appears to be independent of its anti-diabetic action, as experimentally induced diabetes (without treatment) is known to protect against GM-induced nephrotoxicity [51].

Atorvastatin has strong antioxidant properties and has been reported to increase antioxidant capacity and ceruloplasmin [52]. These properties were utilised in antagonizing the ARF induced by GM in rats. Atorvastatin (10 mg/kg/day) significantly attenuated all the immunohistological, histopathological and biochemical indices of the nephrotoxicity of GM (100/kg/day), including tissue oxidative stress parameters. When compared with the control animals, GM-treated rats exhibited more intense expression of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappaB) and inducible NO synthase (iNOS). Concomitant treatment with atorvastatin protected against these changes. It was suggested that this nephroprotection is mediated by scavenging GM-generated free radicals via the inhibition of MAPK and NF-kappaB signalling pathway, in addition to iNOS expression [53].

Rosiglitazone (Rosiglitasone) is a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist with strong antioxidant actions [54]. It has been used to manage diabetes type 2 and some cardiovascular conditions, because it causes vasorelaxation, increased availability of nitric oxide (NO) and also attenuates blood pressure, inflammatory reactions and atherosclerosis [55]. Orally administered rosiglitazone (10 mg/kg/day for 14 days) was effective in reversing the histolopathological and biochemical changes (including indices of oxidative stress) that were induced by GM (100 mg/kg/day for 14 days) given simultaneously [56]. The nephroprotective effect of rosiglitazone is hypothesized to be mediated by its antioxidant action and also by its salutary effect on blood pressure and renal blood flow ascribed to its vasodilatory action. In a recent publication, the related drug pioglitazone actually decreased the activities of antioxidant enzymes and increased lipid peroxidation, suggesting that it can worsen GM nephrotoxicity when given simultaneously [57].

N-Acetylcysteine (NAC), the acetylated derivative of the amino acid L-cysteine, is known to be an excellent source of sulphydryl groups and a precursor of the cyto-protective glutathione (GSH); it is also considered to be a potent detoxifying agent. It has been reported to protect against nephrotoxicity and ototoxicity induced by GM [58]. It was used as a reference agent in an experiment to test the nephroprotective effect of tetramethylpyrazine (TMP) in rats treated with GM [6]. While TMP produced only slight improvement in the GM-induced ARF, NAC (500 mg/kg/day for 10 days, i.p.) completely prevented the measured biochemical and histological alterations induced by the nephrotoxicity and reduced GM in the renal cortex by about 25% [6]. Similar results have recently been reported using NAC at an i.p. dose of 10 mg/kg/day for 7 days [59]. The salutary effect of NAC was ascribed to the strong scavenging properties of NAC.

Agents that augment GM nephrotoxicity

Some of the agents that have been reported to augment GM nephrotoxicity are shown in table 2.

Table 2. 
Some agents that aggravate gentamicin (GM) nephrotoxicity.
AgentDose of agentGM (mg/kg)EffectsReference
Spironolactone20 mg/kg, 6 days, p.o.80, 6 days, i.m.Aggravating effect of GM structural and functional-induced and biochemical signs of GM nephrotoxicity84
Uric acid250 mg/kg, twice daily, 10 days, i.p.80, 10, i.p.GM-induced nephrotoxicity is worsened60
Indomethacinmg/kg, 5 days, p.o.100, 5 days, i.p.GM-induced nephrotoxicity is worsened85

Uric acid.

Using several traditional biochemical techniques and molecular biochemical and histological methods, Romero et al. [60] showed that treatment of rats with uric acid (250 mg/kg, twice daily for 10 days) aggravated the nephrotoxicity of GM (80 mg/kg once daily for 10 days). Uric acid alone did not induce adverse effects on the kidneys. Uric acid is a neuroprotecive agent [61] and a known antioxidant [62], but excessive amounts of serum uric acid have been shown to directly promote oxidative stress [63]. The mechanism of this interaction is not certain, but it was thought that it involved a down-regulation in the activity and expression of the matrix metalloprotease (MMP-2), which are known to mediate acute renal injury and are involved in the alterations in glomeruli and tubular epithelial cells [64]. The clinical significance of this interaction has been stressed, as several diseases and conditions (for example, cardiovascular surgery, tumour lysis syndrome, haemolytic anaemias and acute urate nephropathy) are associated with hyperurcaemia. GM nephroxicity in rats has long been known to increase significantly the uric acid concentration in plasma (for example, Izzettin et al. [65]). This strengthens the case against using GM in conditions when plasma urates are likely to rise.

Verapamil.

The well-established potentiating effect of calcium channel blockers on gentamicin nephrotoxicity in rats [66] and healthy volunteers [67] has recently been reconfirmed by Stojiljkovic et al. [68]. Rats treated daily with verapamil (3 mg/kg/day for 8 days) potentiated some biochemical and histopathological indices of concomitantly administered GM (100 mg/kg/day for 8 days). It should be noted, however, that the effect of some calcium channel blockers on gentamicin nephrotoxicity is not detrimental but rather salutary.

Uranium.

Uranium is a radioactive heavy metal that can accumulate in the proximal renal tubules of humans and animals resulting in several biochemical and morphological signs of nephrotoxicity [69]. It was thought possible that coexposure to uranium and another nephrotoxic agent (for example GM) could aggravate the nephrotoxicity. Chronic exposure to depleted uranium (uranyl nitrate, U238:99.74%, U235: 0.26%, U234: 0.001%, in drinking water for 9 months) has recently been reported by Rouas et al. [70] not to significantly modulate GM nephrotoxicity (5–150 mg/kg given during the last week of uranium exposure subcutaneously). The reason for a lack of a potentiating effect in this experiment is probably due to the low level of exposure to uranium, as this has not caused any significant sign of nephrotoxicity.

Indomethacin.

The coadministration of GM and non-steroidal anti-inflammatory drugs (NSAIDs) is known to result in increased risk of nephrotoxicity [3]. The exact mechanism of this adverse drug interaction is not certain, but it has been confirmed that there is an increased renal synthesis of prostaglandins in GM-induced nephrotoxicity and that NSAID treatment increases prostaglandin synthesis by inhibiting the activity of cyclooxygenase (COX). The net effect of these two actions is deterioration in the glomerular filtration rate of treated subjects. The coadministration of GM with two NSAIDs (namely indomethacin, a non-selective inhibitor of COX 1 and 2, and rofecoxib, a selective inhibitor of COX 2) showed that treatment with indomethacin (at a dose that does not affect renal function) but not rofecoxib, aggravated GM-induced nephrotoxicity. This may be a reflection of the different actions of the two NSAIDs on the enzyme COX and the synthesis of renal prostaglandins [85].

Conclusions

It is known that aminoglycosides (especially GM) can cause nephrotoxicity and ototoxicity, and other antibacterial drugs with equal and sometimes better sensitivity and safety profiles than aminoglycosides are available. Nonetheless, the latter drugs still remain a clinically important group of antibiotics as they have an excellent antibacterial profile against Gram-negative life-threatening infections, and there is more experience with these than with the other newer antibacterial drugs. Even in high-risk groups such as the elderly, these antibiotics are still an important option for infections [71]. A new generation of aminoglycosides has recently been synthesised, and these have an antibacterial profile similar to or better than that of gentamicin [72]. It is not known, however, if the newer aminoglycosides have a similar safety profile to that of the present drugs. Therefore, strategies of ameliorating the toxicity of aminoglycosides are still of clinical interest. In human patients, the single daily injection is probably the only useful approach actually used to mitigate the nephrotoxicity of aminoglycosides. In experimental animals, several strategies to ameliorate the toxicity have been attempted. These include controlling the time of administration of the antibiotics, modifying the diet and coadministering agents to mitigate the renal toxicity. In view of their excellent safety and efficacy profiles, antioxidant drugs were found to produce the best nephroprotection [8]. These agents, especially the natural antioxidants, seem to possess the highest potential for use in the clinic. The ones that showed most safety and efficacy in abating the toxicity should be tested in large controlled clinical trials in humans. Drugs that can possibly impair renal function (for example verapamil, cyclosporine and some diuretics, such as mannitol) should not be given with aminoglycoside drugs, to avoid potentiation of the nephrotoxicity.

Acknowledgements

Thanks are due to Ms Intisar Al- Lawati and Ms Somyia Beegam for their help with some of the references.

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