Ramzi Sabra

Amphotericin B Nephrotoxicity

SummaryThe frequency of fungal infections is increasing. Amphotericin B remains the antifungal drug of choice for most systemic infections, but a limiting factor for its use is the development of nephrotoxicity. Amphotericin B-induced nephrotoxicity is manifested as azotaemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities like hypokalaemia and sodium and magnesium wasting. All these abnormalities occur to varying degrees in almost all patients receiving the drug. Upon withdrawal of therapy renal function gradually returns to baseline, although in some instances permanent damage is sustained, especially when the cumulative dose exceeds 5g. Salt depletion enhances the development of nephrotoxicity. The mechanism of nephrotoxicity involves direct cell membrane actions to increase permeability, as well as indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and filtration rate, responses that are inhibited by several physiological and pharmacological interventions. Changes in intracellular calcium levels may also contribute to the observed effects.In the clinical situation, and in long term models of nephrotoxicity in the rat, salt loading protects against deterioration in renal function; recommendations are made for the optimisation of amphotericin B therapy by salt loading. New preparations of the drug, such as liposomal amphotericin B, may also prove useful in minimising nephrotoxicity while maintaining antifungal activity, but further research is needed with both salt loading and liposomal amphotericin B to confirm or deny their protective effect on kidney function.

Using team-based learning to teach pharmacology to second year medical students improves student performance

Background: Team-based learning (TBL) is an innovative instructional method that fosters active learning. It has been shown to improve student performance in some health care education courses. Aim: To examine the effect of teaching pharmacology using a TBL approach on second year medical students’ satisfaction and performance. Methods: A modified TBL method was used in two case-based discussion sessions of the second year pharmacology course: a relatively easy drug metabolism/pharmacogenetics session and a more challenging pharmacokinetics/pharmacodynamics (PK/PD) session. Individual and group answers to all questions were recorded, and an evaluation form was collected for each session. Class performance on a summative quiz was compared to previous years. Results: Students provided positive feedback. Group performance was better than individual performance during the TBL exercises. TBL was less successful when the questions were very difficult, with a difficulty range of 30–70% being the most appropriate. Performance of the class on the pharmacology summative quiz showed significant improvement over that in previous years in the PK/PD part, but was unchanged in other topics taught traditionally. Conclusion: The results suggest that TBL provides a better outcome for students, and provide insight into appropriate design of TBL exercises.

Drug‐related hospitalization at a tertiary teaching center in Lebanon: Incidence, associations, and relation to self‐medicating behavior

In Lebanon there is very limited restriction on drug use. Accordingly, self‐medication is highly prevalent. This study examined the influence of these factors on the development of drug‐related illnesses that lead to hospitalization.

Using Team-based Learning to Teach Clinical Pharmacology in Medical School: Student Satisfaction and Improved Performance

Formal teaching in clinical pharmacology was never part of the curriculum at the American University of Beirut Faculty of Medicine. Based on feedback from students and on recommendations of academic bodies, we have introduced, since June 2008, twice‐monthly “rational prescribing” sessions during the required internal medicine rotation in year 4 of medical school. All sessions were designed according to the innovative Team‐based Learning format and concluded by having the students practice prescription writing and personal formulary development based on the World Health Organization criteria. Our 18‐month experience showed that students were very satisfied with the course and the teaching approach, and that their performance on prescription writing and formulary development had improved. Although further studies are needed to explore the impact of team‐based learning on additional performance measures, we recommend it as an effective alternative for teaching clinical pharmacology in medical schools.

Alternating ibuprofen and acetaminophen in the treatment of febrile children: A pilot study [ISRCTN30487061]

BackgroundAlternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of a single administration of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children.MethodsSeventy febrile children were randomly allocated to receive either a single oral dose of 10 mg/kg ibuprofen and 15 mg/kg oral acetaminophen after 4 hours, or a similar dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline, 4, 5, 6, 7 and 8 hours later. Endpoints included proportions of afebrile children at 6, 7 and 8 hours, maximum decline in temperature, time to recurrence of fever, and change in temperature from baseline at each time point. Intent-to-treat analysis was planned with statistical significance set at P < 0.05.ResultsA higher proportion of subjects in the intervention group (83.3%) became afebrile at 6 hours than in the control group (57.6%); P = 0.018. This difference was accentuated at 7 and 8 hours (P < 0.001) with a significantly longer time to recurrence of fever in the intervention group (mean ± SD of 7.4 ± 1.3 versus 5.7 ± 2.2 hours), P < 0.001. Odds ratios (95%CI) for defervescence were 5.6 (1.3; 23.8), 19.5 (3.5; 108.9) and 15.3 (3.4; 68.3) at 6, 7 and 8 hours respectively. Two-way ANOVA with repeated measures over time revealed a significantly larger decline in temperature in the intervention group at times 7 (P = 0.026) and 8 (P = 0.002) hours.ConclusionA single dose of alternating ibuprofen and acetaminophen appears to be a superior antipyretic regimen than ibuprofen mono-therapy. Further studies are needed to confirm these findings.

Taurine Intestinal Absorption and Renal Excretion Test in Diabetic Patients: A pilot study

There is evidence that diabetes is characterized by taurine deficiency (1–4), which has been linked to diabetic retinopathy, neuropathy, and nephropathy (5–7). Taurine is involved in neuronal modulation, osmoregulation (8), and protection against oxidative stress (9). Its plasma levels are maintained within a normal range through protein intake, and de novo synthesis is limited by the activity of hepatic cysteinesulphinic acid decarboxylase, which is low in humans. Taurine depletion can occur rapidly (10), possibly leading to retinal, cardiac, neural, immune, and hemostatic dysfunction (4,11–14). The reasons for taurine deficiency in diabetes remain unclear. A decrease in the overall body pool (1,2) and/or internal redistribution between the intra- and extracellular compartments are possibilities. The former can be secondary to decreased oral intake, poor intestinal absorption, renal wasting, or a combination of factors. In diabetic rats, intestinal absorption of taurine is reduced (K.B., Camille Nassar, unpublished data), while urinary taurine excretion is enhanced (15). Kidney loss in uncontrolled diabetes is aggravated by severe hyperglycemia and ketoacidosis (4). Data are lacking, however, on urinary excretion and pharmacokinetics of taurine absorption in human diabetes with mild-to-moderate hyperglycemia. This pilot study was therefore conducted in patients with moderately impaired glucose control and in matched nondiabetic subjects to evaluate the pharmacokinetics of taurine absorption following an oral load and to elucidate the mechanism of taurine deficiency in diabetes. A total of 16 subjects were enrolled in the study: 6 patients with type 2 diabetes, 2 with type 1 diabetes, and 8 healthy subjects; subjects were pair-matched for age, sex, and BMI. …

Potassium depletion potentiates amphotericin-B-induced toxicity to renal tubules.

Hypokalemia and potassium depletion are frequent complications of amphotericin B therapy. Both ischemic and gentamicin-induced renal failure is potentiated by potassium depletion; it is, therefore, possible that amphotericin B nephrotoxicity is similarly influenced. This study evaluated whether the acute nephrotoxic response to amphotericin B is potassium sensitive. Potassium-depleted and control rats were subjected to an acute intravenous infusion of either amphotericin B (AmB-K; AmB, n = 10 in each) or its vehicle (V-K, V; n = 6 in each). Potassium-depleted rats had both lower urinary daily excretion and lower plasma levels of potassium than control animals (0.1 +/- 0.0 vs. 2.1 +/- 0.2 mEq/day, p < 0.001, and 3.8 +/- 0.2 vs. 1.9 +/- 0.1 mEq/l, p < 0.001, respectively). In AmB and AmB-K groups, there were equivalent falls in glomerular filtration rate and renal blood flow, and a rise in renal vascular resistance, compared with V and V-K. In contrast, the AmB-K group showed a higher urinary excretion of sodium (AmB-K vs. AmB: 2.9 +/- 0.7 vs. 1.1 +/- 0.3 microEq/min; p < 0.05) and fractional excretion of Na (AmB-K vs. AmB: 1.6 +/- 0.4 vs. 0.6 +/- 0.1%; p < 0.05) in comparison to the AmB group. Neither of these parameters changed in either amphotericin B or vehicle-treated groups. These results suggest that potassium depletion does not influence the acute renovascular effects of amphotericin B but potentiates its tubular toxicity. This may have clinical implications since hypokalemia and potassium depletion are frequent complications of amphotericin B therapy.

Sodium status influences chronic amphotericin B nephrotoxicity in rats.

The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats.

Blockade of endothelin ETA, but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions

The impairment of arterial baroreceptor and vasodilator functions are two major contributors to the hypertensive action of cyclosporine (CSA). In this study, in vivo and in vitro pharmacological studies were performed to investigate whether these effects of CSA are differentially modulated by endothelin and thromboxane signaling. The treatment of rats with CSA (25mg/kg/day i.p.) for 7 consecutive days caused significant increases in blood pressure (BP), attenuated reflex heart rate (HR) responses to vasopressor (phenylephrine, PE) and vasodepressor (sodium nitroprusside, SNP) agents, and reduced cumulative vasorelaxant responses elicited by acetylcholine (Ach, 1×10(-9)-1×10(-5)M) in PE-precontracted isolated aortas. These effects of CSA were blunted after concurrent i.p. administration of atrasentan (selective ETA blocker, 10mg/kg/day), but not terutroban (thromboxane receptor blocker, 10mg/kg/day). Moreover, atrasentan reversed the reductions in aortic protein expression of eNOS caused by CSA whereas terutroban was without effect. We also report that the favorable effect of atrasentan on CSA-evoked impairment in aortic Ach responsiveness disappeared in rats treated simultaneously with L-NAME (NOS inhibitor, 10mg/kg/day) but not BQ 788 (ETB receptor blocker, 0.1mg/kg/day) or indomethacin (cycloxygenase inhibitor, 5mg/kg/day). Together, the data implicate endothelin ETA receptors in baroreflex and vascular derangements which predispose to the hypertensive effect of CSA. Moreover, the facilitation of NOS, but not ETB receptors or cycloxygenase-derived prostanoids, signaling is pivotal for advantageous effect of atrasentan on the aortic CSA-Ach interaction.

Temporal changes in vascular reactivity in early diabetes mellitus in rats: role of changes in endothelial factors and in phosphodiesterase activity.

The aims of this study were to study the influence of the duration of diabetes, the role of endothelial-derived vasodilators, and the role of phosphodiesterase (PDE) isoform activity in the early changes in vascular reactivity of aortic rings from diabetic rats. Diabetes mellitus was induced in female rats by intravenous streptozotocin (85 mg/kg). Two or 4 wk later, thoracic aortic rings from control and diabetic rats were isolated, and vascular responses to acetylcholine (ACh), S-nitroso-N-acetylpenicillamine (SNAP) [nitric oxide (NO) donor], DMPPO (PDE5 inhibitor), and phenylephrine (PE) were obtained in the presence and absence of endothelium or other drugs. PDE isoform activity was also measured. At 2 wk, responses to ACh and DMPPO were enhanced, whereas those to PE were attenuated in diabetic rats relative to controls. Indomethacin and SQ-29548 (a thromboxane A(2) receptor antagonist), but not N(G)-nitro-L-arginine methyl ester, corrected these differences. The responses to SNAP, and cAMP and cGMP hydrolytic activities, were similar in the two groups. In contrast, at 4 wk, ACh, DMPPO, and PE produced similar responses in the two groups: N(G)-nitro-L-arginine methyl ester rendered the response to PE lower in the diabetic group, and this was corrected by indomethacin, but not SQ-29548, treatment. The response to SNAP was greater in the diabetic group, and this was corrected by DMPPO. Activity of all PDEs was decreased at 4 wk. We conclude that, at 2 wk, there is modulation of thromboxane A(2) production, but no change in the NO system or PDE isoform activities. At 4 wk, a reduction in NO activity is superimposed; at this stage, PDE activity is reduced, together with increased production of vasodilating prostaglandins, possibly as a compensatory mechanism to maintain normal vascular reactivity.