Michael Spino

Colchicine: a state-of-the-art review.

Colchicine is an ancient drug that is attracting renewed interest because of its actions at a subcellular level. Specifically, it interferes with microtubule growth and therefore affects mitosis and other microtubule‐dependent functions. Various mechanisms have been proposed to account for the action of colchicine in acute gouty arthritis, its interaction with cellular membrane and cyclic 3′,5′‐adenosine monophosphate, and its action in amyloidosis. Pharmacokinetic studies have been relatively limited and their results somewhat contradictory, with mean terminal elimination half‐lives of 19 minutes to 9 hours being reported. Some of these differences may be attributed to assay difficulties. Colchicine can cause gastrointestinal side effects and should be used with care to protect patients from toxic doses. Colchicine‐induced myopathy and neuropathy may be more frequent than previously recognized, and therefore patients receiving long‐term therapy should be monitored carefully. Bone marrow depression has been reported, primarily in cases of acute colchicine intoxication, and intravenous administration of the drug has been associated with severe pancytopenia and death. Colchicine intoxication causes multiple organ failure. Because of its cytogenic effects and reported association with Downs syndrome, the agent should not be used by pregnant women.

Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

Ceftazidime disposition in acute and stable cystic fibrosis

Ceftazidime disposition after an intravenous dose of 50 mg/kg infused over 20 min was followed in 10 subjects with cystic fibrosis (CF) hospitalized with acute pulmonary exacerbations and in 10 healthy subjects. Serum ceftazidime elimination t½ decreased from 105.3 ± 12.4 min (X̄ ± SD) in controls to 90.0 ± 11.1 min in subjects with CF. Calculated distribution volumes were both larger in subjects with CF. When normalized for body surface area, total body clearance (Cl) was 41.9% greater in the CF group (142.4 ± 16.9 and 100.5 ± 10.3 ml/min/1.73 m2). Normalization for body weight revealed 64.8% greater Cl in subjects with CF. Fraction of dose recovered in urine was of the same order for each group, while renal clearance (ClR) was 40.9% greater in the subjects with CF (130.1 ± 11.4 and 92.7 ± 11.6 ml/min/1.73 m2). Five subjects with CF were restudied while infection‐free 119 to 219 days after the original study day. With the exception of a 10% increase in the volume of distribution at steady state while infection‐free, kinetic parameters were much the same. No changes in Cl or ClR were evident from one study day to the next. Acute pulmonary infection does not appear to alter ceftazidime clearance in CF. The mechanism underlying increased ceftazidime Cl and ClR in CF is not apparent from the present data.

Cloxacillin absorption and disposition in cystic fibrosis

Because of reports of lowered antibiotic serum concentrations in patients with cystic fibrosis (CF), a bioavailability and pharmacokinetic study of cloxacillin was conducted in 12 control and 16 patients with CF after intravenously and orally administered doses of cloxacillin 25 mg/kg. The patients had mild to moderate CF and were in stable condition. Significantly lower serum concentrations in CF were a result of a 78% increase in total body clearance (P less than 0.005) and a 38% increase in the apparent volume of distribution (P less than 0.025). The bioavailability in CF (0.50) was not significantly different than in controls (0.38), but more variability was seen in the group with CF. After the intravenously given dose the fraction of cloxacillin excreted in the urine unchanged was similar in controls (0.644) and patients with CF (0.547). Compared with that in the control subjects, the mean renal clearance in patients with CF was 30% greater (P less than 0.10) and the nonrenal clearance was 144% greater (P less than 0.07). Enhanced nonrenal clearance explains most of the demonstrated difference between serum concentrations in controls and patients with CF after identical weight-adjusted doses. The data suggest enhanced cloxacillin biotransformation in CF.

The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration.

PURPOSE Iron-induced oxidative stress may exacerbate age-related macular degeneration (AMD). Ceruloplasmin/Hephaestin double-knockout (DKO) mice with age-dependent retinal iron accumulation and some features of AMD were used to test retinal protection by the oral iron chelator deferiprone (DFP). METHODS Cultured retinal pigment epithelial (ARPE-19) cells and mice were treated with DFP. Transferrin receptor mRNA (Tfrc), an indicator of iron levels, was quantified by qPCR. In mice, retinal oxidative stress was assessed by mass spectrometry, and degeneration by histology and electroretinography. RESULTS DFP at 60 μM decreased labile iron in ARPE-19 cells, increasing Tfrc and protecting 70% of cells against a lethal dose of H(2)O(2). DFP 1 mg/mL in drinking water increased retinal Tfrc mRNA 2.7-fold after 11 days and also increased transferrin receptor protein. In DKOs, DFP over 8 months decreased retinal iron levels to 72% of untreated mice, diminished retinal oxidative stress to 70% of the untreated level, and markedly ameliorated retinal degeneration. DFP was not retina toxic in wild-type (WT) or DKO mice, as assessed by histology and electroretinography. CONCLUSIONS Oral DFP was not toxic to the mouse retina. It diminished retinal iron levels and oxidative stress and protected DKO mice against iron overload-induced retinal degeneration. Further testing of DFP for retinal disease involving oxidative stress is warranted.

Pharmacokinetics of Drugs in Cystic Fibrosis

Considerable work has been conducted on patients with CF to clearly demonstrate enhanced clearances of many, but not all drugs. The precise mechanisms for enhanced drug clearance in CF remain to be elucidated, and it will be important to examine the two major organs of drug elimination, the kidney and liver, for answers to these questions. Although it has not been studied to date, the role of the lung as a contributor to enhanced drug clearance in CF needs to be considered as well. In the liver it appears that both hepatic biotransformation as well as biliary excretion may be enhanced. In the kidney, there is enhanced CLr of acidic drugs, but variable findings for cationic and zwitterionic drugs. The latter finding can be explained on the basis of the pKa of the drugs and the urine pH. It would be most appealing if enhanced renal and nonrenal clearance of drugs in CF could be attributed to a common single defect. At this time, there is no obvious candidate, although altered transmembrane transport would represent a place to start.

Neonatal withdrawal syndrome: associated drugs and pharmacologic management.

Use of addicting drugs among women during pregnancy exposes newborns to potentially serious disorders. A group of symptoms referred to as neonatal withdrawal syndrome (NWS) may occur in infants born to mothers addicted to certain drugs because, at birth, the infants suddenly are cut off from the drug supply. Classes of drugs that cause NWS are those that produce addiction in adults, including the opioids (heroin, methadone, morphine), barbiturates, alcohol, and benzodiazepines. Many of the manifestations of NWS occur regardless of the class of drug, including irritability, hyperactivity, abnormal sleep pattern, high‐pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The fact that these symptoms are nonspecific makes it difficult to identify NWS unless it is specifically looked for. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mothers last dose, and rate of elimination of the drug from the newborn. Pharmacologic intervention may be required to control severe symptoms and signs. The most common drugs used to modify withdrawal are phenobarbital, paregoric, chlorpromazine, and diazepam. Treatment is complicated by conflicting information on the effectiveness of various agents.

Deferiprone in Friedreich ataxia: A 6-Month randomized controlled trial.

We conducted a 6‐month, randomized, double‐blind, placebo‐controlled study to assess safety, tolerability, and efficacy of deferiprone in Friedreich ataxia (FRDA).

Pulse dosing versus continuous infusion of antibiotics. Pharmacokinetic-pharmacodynamic considerations

SummaryThe issue of whether it is better to administer antibiotics as an intermittent bolus dose or a continuous intravenous infusion has been debated for several decades. This paper reviews the extensive literature on the topic, considering both the pharmacokinetic and pharmacodynamic aspects of antibacterials as well as experimental results from studies conducted in vitro, in animals and in humans. It is evident from reviewing the literature that neither mode of administration is clearly superior to the other. The decision regarding the mode of administration must take into account the antibiotic being used, the bacteria, the patient and the infection, as well as the pharmacokinetics of the particular drug in the individual patient. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) are useful indicators of the relative in vitro effectiveness of antibiotics, but it is not clear what relevance these parameters have to the desired antibiotic concentrations in vivo. Furthermore, questions of serum vs tissue fluid concentrations, peak concentrations vs AUC, and free vs total concentration are all important issues to consider in assessing the optimal mode of administration. The importance of newer indices such as the post-antibiotic effect are now beginning to be recognised.A number of scientists are actively engaged in developing a system to identify the most appropriate mode of administration based upon the integration of an antibiotic’s pharmacodynamics and pharmacokinetics. Within the next few years we anticipate that appropriate guidelines should have been developed to aid the optimisation of parenteral administration, at least for some antibiotics.

Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis.

A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.