The ulnar nerve in the cubital tunnel: a foetal study.

BACKGROUND: The ulnar nerve (UN), a terminal branch of the medial cord of the brachial plexus, is located posteromedial to brachial artery coursing along medially in the arm from the anterior to the posterior compartment through the arcade of Struthers. It passes posterior to medial epicondyle of humerus and enters the cubital tunnel. Then, it exits through the distal part of the cubital fossa to enter the medial side of the forearm between the two heads of the flexor carpi ulnaris muscle underneath Osborne's ligament to enter the anterior compartment of the forearm. Entrapment of the UN at the cubital tunnel results in a pain and a tingling sensation on the medial side of the forearm and fourth and fifth digits. MATERIALS AND METHODS: This foetal study documented the course of the UN within the cubital tunnel and its anatomical relations utilising bilateral microscopic dissection of 25 foetuses (gestational age: 19-36 weeks). RESULTS: The UN followed the standard anatomical course in 96% (48/50) of the specimens, however it was found to lie deep to the muscles of the cubital tunnel in 6% (3/50). The radial artery joined the UN distal to the cubital tunnel in 8% (4/50), while the superior ulnar collateral artery was posteriorly related to the UN in 32% (16/50) of specimens. The Osborne's ligament (crossed between the two heads of the flexor carpi ulnaris muscle, posterior to the medial epicondyle of the humerus) was present in all specimens 100% (50/50). It had a mean length of 6.32 ± 0.97 mm and 6.30 ± 1.10 mm on the left and right sides, respectively. The current study observed that the flexor pronator aponeurosis was present in 2% (1/50) of specimens. CONCLUSIONS: Knowledge of the normal and variable anatomical course of the UN in the cubital tunnel in this study may assist in the diagnosis and treatment of compressive neuropathy of the UN in the cubital tunnel.

Effect of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro.

The effects of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro was investigated. Acetaminophen, lidocaine, phenobarbital, quinidine, theophylline, and valproic acid were added to pooled human serum at therapeutic concentrations. To each preparation was added one additional drug at three concentrations ranging from therapeutic to toxic. The following eight target drug/added drug combinations were studied: acetaminophen/phenobarbital. acetaminophen/theophylline, lidocaine/quinidine, phenobarbital/acetaminophen, phenobarbital/valproic acid, quinidine/lidocaine, theophylline/acetaminophen, and valproic acid/phenobarbital. Each serum without the other added drug as well as the serum supplemented with the other drug at the three concentrations was dialyzed against phosphate buffer. Similarly dialyzed were phenobarbital, quinidine, and theophylline, both alone at therapeutic concentrations in serum and with ethanol at three different concentrations in serum. The percentage of drug binding in each preparation was calculated. Acetaminophen diminished the binding of theophylline to human serum by a net change of 5.7% (percentage increase in free drug fraction [FDF], 11.0%) at 662 micromol/L and by a net change of 7.1% (percentage increase in FDF, 13.7%) at 1324 micromol/L. Theophylline decreased the binding of acetaminophen by a net change of 6.8% (percentage increase in FDF, 8.8%) at 277.5 micromol/L; phenobarbital reduced it by a net change of 6.6% (percentage increase in FDF, 8.5%) at 431 micromol/L. Valproic acid diminished binding of phenobarbital by a net change of 9.9% (percentage increase in FDF, 21.2%) at 1732 micromol/L. No significant effects were noted with other drug combinations or with the addition of ethanol. Coingestion of acetaminophen with theophylline, phenobarbital with acetaminophen, and valproic acid with phenobarbital at high to toxic concentrations decreases the binding of the target drug. The resulting increase in free drug concentration may lead to enhanced drug effect in vivo.

Cocaine and cocaethylene binding to normal human brain and Alzheimer disease brain.

The binding of cocaine and cocaethylene to homogenates of both normal whole brain and whole brain with Alzheimer disease patients (Alzheimer brain) was investigated in vitro using equilibrium dialysis of the unlabelled drugs at 4 degrees C. Two binders of cocaine were characterized in normal brain (binder 1: Ka, 5.73 x 10(3) L/mol; Bo, 7.44 x 10(-5) mol/L) (binder 2: Ka, 1.54 x 10(3) L/mol; Bo, 2.50 x 10(-4) mol/L) and in Alzheimer brain (binder 1: Ka, 3.08 x 10(2) L/mol; Bo, 6.66 x 10(-4) mol/L) (binder 2: Ka, 8.74 x 10(1) L/mol; Bo, 4.30 x 10(-3) mol/L). For cocaethylene three binders were noted in normal brain (binder 1: Ka, 3.23 x 10(3) L/mol; Bo, 1.22 x 10(-4) mol/L) (binder 2: Ka, 3.10 x 10(3) L/mol; Bo, 2.01 x 10(-4) mol/L) (binder 3: Ka, 1.63 x 10(3) L/mol; Bo, 3.59 x 10(-4) mol/L) and two binders in Alzheimer brain (binder 1: Ka, 5.18 x 10(3) L/mol; Bo, 3.06 x 10(-5) mol/L) (binder 2: Ka, 3.36 x 10(3) L/mol; Bo, 7.75 x 10(-5) mol/L). The binding of cocaine to normal brain was much stronger than to Alzheimer brain (ten- to 100-fold), whereas the binding of cocaethylene was similar in normal and Alzheimer brain. Cocaine and cocaethylene binding to human brain was compared with cocaine and cocaethylene binding to other human tissues previously studied by this laboratory.

Binding of antiarrhythmic drugs to human placenta in vitro.

Lidocaine, procainamide and quinidine binding to human placenta was investigated in vitro. Pooled whole human placental homogenate supplemented with either non-radiolabelled lidocaine, procainamide or quinidine over the concentration range 50-5,000 x 10(-7) mol/L was submitted to equilibrium dialysis against phosphate buffer, pH 7.4, 0.1 mol/L. Post-dialysis drug concentrations were measured by enzyme immunoassay. Data were analyzed by the method of Scatchard. No binding to placenta was noted for either lidocaine or procainamide. In contrast, up to 22 percent of quinidine was bound. Two binders were defined as follows: #1 (Ka, 7.37 x 10(5) L/mol; Bo, 1.55 x 10(-7) mol/L) and #2 (Ka, 7.11 x 10(4) L/mol; Bo, 4.05 x 10(-6) mol/L). The concentrations of quinidine binding sites in moles per gram of placenta were 1.55 x 10(-9) and 4.05 x 10(-8), respectively. These data suggest that quinidine may be accumulated in human placenta.

Quinidine inhibition of cocaethylene degradation in human serum in vitro: a preliminary study.

Quinidine (QUINID) substantially inhibited the serum degradation of cocaethylene (CE), an important cocaine analog, when incubated for two hours at 37 degrees C with pooled human serum containing 1.58 micromol/L of CE. In the absence of QUINID, the CE concentration was only 49.4% of its original value after incubation. However, QUINID at subtherapeutic (3.08 micromol/L) and therapeutic (15.4 micromol/L) concentrations preserved 55.1% and 75.9% of the original CE concentration, respectively. At a QUINID concentration of 308 micromol/L, 89.2% of the CE concentration was preserved. There was a marked decrease in the serum cholinesterase (CHE) activity as QUINID concentrations were increased to 154 micromol/L (19.8% decrease in CHE) and to 308 micromol/L (36.8% decrease in CHE). These data suggest that QUINID inhibits the hydrolysis of CE in human serum by suppressing CHE activity. These findings are significant because QUINID may be used in patients who have abused cocaine with ethanol. They also have important implications for individuals receiving QUINID together with other drugs whose hydrolysis may be catalyzed by CHE.

Procainamide inhibition of human hepatic degradation of cocaine and cocaethylene in vitro.

Procainamide (PA), a cardioactive drug, inhibited the degradation of both cocaine (COC) and cocaethylene (CE) when either was incubated in human liver homogenates for 3 h at 37 degrees C. PA appeared to enhance the formation of CE when COC and ethanol (ETOH) were incubated together in liver homogenate. These observations are clinically significant because cardiotoxicity is common after COC abuse and because PA may be administered to individuals who use COC alone and with ETOH.

Amitriptyline and procainamide inhibition of cocaine and cocaethylene degradation in human serum in vitro.

Amitriptyline (AMI) and procainamide (PA) have been reported to inhibit the activity of human plasma butyrylcholinesterase, an enzyme important in the metabolic degradation of cocaine (COC) and its ethyl analogue cocaethylene (CE). Because both AMI and PA may be used in the treatment of COC intoxication and abuse, the effect of high pharmacological concentrations of these compounds on the degradation of COC and CE in pooled human serum was studied. AMI (1.8 micromol/L) modestly inhibited the degradation of COC by 4.2% and of CE by 4.0%. PA (42.5 micromol/L) profoundly inhibited degradation of COC by 42.7% and of CE by 47.2%. In contrast, lithium carbonate (1 mmol/L, control) showed no inhibition of degradation of either COC or CE. These results suggest that AMI and PA may prolong the half-life of COC and CE in human serum.

Relative binding of therapeutic drugs by sera of seven mammalian species.

The relative binding of acetaminophen, lidocaine, phenobarbital, procainamide, quinidine, and theophylline to sera of seven mammalian species was studied. Pooled commercial sera from cow, goat, horse, human, pig, rabbit, and sheep were supplemented with 5 and 10 mM concentrations of each drug. For each serum, each drug, and each drug concentration, equilibrium dialysis was performed in duplicate against phosphate buffer (pH 7.4, 0.1 M, 4 degrees C). Percent drug bound to serum was calculated. Phenobarbital demonstrated more than 20% binding to goat, horse, human, and sheep serum at both 5 and 10 mM concentrations; more than 20% binding to bovine serum at a concentration of 10 mM; and more than 20% binding to pig and rabbit serum at 5 mM. Quinidine (studied only at 5mM concentration) bound more than 20% to cow, goat, horse, human, pig, and rabbit serum. In contrast, procainamide at both the 5 and 10 mM concentrations showed no binding to cow, horse, pig, rabbit, or sheep serum. Acetaminophen (studied only at 5 mM concentration), lidocaine, and theophylline demonstrated less than 20% binding to each serum. Acetaminophen at 5 mM did not bind to human serum, and lidocaine at 10 mM did not bind to horse or pig serum. Although some interspecies variation in drug binding to the seven sera was noted, the overall magnitude of binding of each drug to each serum was, for the most part, similar. Phenobarbital and quinidine showed stronger (> 20%) binding; procainamide showed negligible binding; and acetaminophen, lidocaine, and theophylline demonstrated intermediate (< 20%) binding.

Cocaine and cocaethylene binding to human milk.

The binding of cocaine and its ethyl analog, cocaethylene, to human milk was studied using equilibrium dialysis at 4 degrees C. For cocaine, a low-affinity, high-capacity binder was noted (equilibrium constant of association, Ka, 3.12 x 10(3) L/mol; concentration of binding sites, B0, 3.85 x 10(-4) mol/L), as well as a very low affinity, high-capacity binder (Ka, 7.54 x 10(2) L/mol; B0, 1.42 x 10(-3) mol/L). For cocaethylene, 2 low-affinity, high-capacity binders were suggested: a stronger (Ka, 3.79 x 10(3) L/mol; B0, 3.27 x 10(-4) mol/L) and a weaker (Ka, 1.84 x 10(3) L/mol; B0, 8.91 x 10(-4) mol/L) binder The low-affinity, high-capacity binder for cocaine and cocaethylene seems to be albumin, while the weaker nonspecific binding may be due to lipids. Up to 55% of cocaine and up to 61% of cocaethylene were bound to milk; such binding, coupled with the lower pH of milk (6.9) relative to that of serum (7.4), may enhance the mammary secretion of these 2 basic drugs, having important consequences for the nursing infant.

Lidocaine, quinidine, and theophylline binding to human milk.

Lidocaine, quinidine, and theophylline binding to normal pooled mature human milk was determined using equilibrium dialysis at 4 degrees C. Binding to milk was compared with binding to pooled human serum. The observed binding was related to the relative lipid solubility of each drug in milk. The potential for the excretion of each drug into milk was also evaluated.

Cocaine and cocaethylene binding to human liver.

The binding of cocaine (COC) and cocaethylene (CE) to whole human liver homogenates in vitro was studied by equilibrium dialysis. Drugs were measured by high-pressure liquid chromatography. Up to 32% of COC and up to 43% of CE were bound. Scatchard analysis suggested a high-affinity, low-capacity binder for both COC (Ka, 4.69 x 10(4) L/mol; Bo, 1.08 x 10(-5) mol/L) and CE (Ka, 4.38 x 10(4) L/mol; Bo, 1.54 x 10(-5) mol/L). In addition, low-affinity, high-capacity binders for COC (Ka, 2.93 x 10(3) L/mol; Bo, 1.32 x 10(-4) mol/L) and CE (Ka, 6.50 x 10(3) L/mol; Bo, 1.11 x 10(-4) mol/L) were noted. Finally, for both compounds, very low-affinity, high-capacity binding, which was likely nonspecific in nature, was defined as follows: COC, Ka, 8.00 x 10(2) L/mol; Bo, 5.45 x 10(-4) mol/L and CE, Ka, 2.10 x 10(3) L/mol; Bo, 3.71 x 10(-4) mol/L. The binding profiles of COC and CE in liver were compared with those in human serum and placenta studied previously by this laboratory.

Cocaine and cocaethylene binding to human placenta in vitro.

OBJECTIVE: The aim of the study was to determine the binding profiles of cocaine and its ethyl homolog, cocaethylene, in human placenta. STUDY DESIGN: Pooled whole human placental homogenates supplemented with either nonlabeled cocaine or cocaethylene over the concentration range 10 to 5000 x 10(-7) mol/L were submitted for equilibrium dialysis. Drug concentrations were measured by high-pressure liquid chromatography. Scatchard analysis of the data was performed. RESULTS: A high-affinity, low-capacity binder was identified for cocaine (equilibrium constant of association, 3.68 x 10(5) L/mol; concentration of binding sites, 4.36 x 10(-6) mol/L) and for cocaethylene (equilibrium constant of association, 2.42 x 10(4) L/mol; concentration of binding sites, 2.65 x 10(-5) mol/L). Also, a low-affinity, high-capacity binder was noted for cocaine (equilibrium constant of association, 1.93 x 10(3) L/mol; concentration of binding sites, 5.28 x 10(-4) mol/L) and for cocaethylene (equilibrium constant of association, 2.15 x 10(2) L/mol; concentration of binding sites, 2.65 x 10(-3) mol/L). The concentration of binding sites expressed as moles per gram of placenta was as follows: high-affinity binder (cocaine, 4.36 x 10(-8); cocaethylene, 2.65 x 10(-7) and low-affinity binder (cocaine, 5.28 x 10(-6); cocaethylene, 2.65 x 10(-5). Up to 59% of cocaine and up to 42% of cocaethylene was bound. CONCLUSION: Human placenta may serve as a depot for cocaine and cocaethylene.

Effect of drugs and cocaine metabolites on cocaine and cocaethylene binding to human serum in vitro.

The effect of amphetamine (AMPH), codeine (COD), methamphetamine (MEPH), morphine (MORP), and benzoylecgonine (BE) on the binding of cocaethylene (CE) and cocaine (COC) to human serum in vitro was investigated by equilibrium dialysis at 4 degrees C. Each compound was added individually at concentrations of 500, 1,000, or 2,000 nM to pooled human serum containing COC or CE at 500 nM concentration. For COC, the addition of COD, MEPH, and CE enhanced serum binding whereas MORP and BE decreased it. Variable effects on COC binding were noted for AMPH. For CE, the addition of COD and COC generally increased binding whereas MORP decreased it. No appreciable effect on CE binding was observed after adding AMPH, MEPH, and BE. Except for CE, AMPH, and MEPH in the presence of COC, the binding of COC and CE tended to be less with 2,000 nM of each added drug than at lower concentrations of them, presumably because of mass-action displacement of COC and CE at the higher concentration. These findings should be clinically important because these drugs are frequently found together in patients.

Relative binding of acetaminophen, lidocaine, phenobarbital, phenytoin, quinidine, and theophylline to human tissues in vitro.

The relative binding of acetaminophen, lidocaine, phenobarbital, phenytoin, quinidine, and theophylline to human tissues in vitro was studied using equilibrium dialysis. Pooled human serum plus homogenates of brain, heart, liver, and placenta were incubated at 4 degrees C with each drug at concentrations of 5 and 10 mmol/L. The percent binding of each drug to each tissue was calculated. Binding of 5% or less was considered to be negligible. By drug, the following relative binding orders were observed for those tissues demonstrating binding: acetaminophen (heart > brain, serum); lidocaine (no appreciable binding observed); phenobarbital (serum only); phenytoin (heart and liver equally; serum not studied); quinidine (serum > liver > brain, placenta); and theophylline (serum > liver). By matrix, serum bound all drugs studied except for lidocaine. Liver bound only phenytoin, quinidine, and theophylline; heart bound only acetaminophen and phenytoin; brain bound only acetaminophen and quinidine; and placenta bound only quinidine.

Cocaine- and cocaethylene-creatinine clearance ratios in humans.

Cocaine (COC)- and cocaethylene (CE)-creatinine clearance ratios (CCR) were determined in five patients. In each case, COC:CCR greatly exceeded CE:CCR, and in four patients the data suggested renal tubular secretion of COC. For all patients, some renal tubular reabsorption of CE was apparent. These findings may be due, at least in part, to the greater hydrophobicity of CE relative to COC and to the lower pKb of CE (8.23) than that of COC (8.60). The pKb of CE was determined by titrimetry and is reported here for the first time. These data may be useful in investigating the pharmacokinetic profiles of COC and CE in humans and may also help to explain the longer plasma half-life of CE relative to that of COC.

Comprehensive review of cocaethylene and cocaine concentrations in patients.

Cocaethylene (CE) and cocaine (COC) concentrations were reviewed for 41 patients studied by this laboratory and found to have measurable CE in plasma. In 17 instances, urine concentrations of CE and COC were also measured. In 15 cases other drugs in addition to COC and ethanol (ETOH) were detected. Thirty-three cases involved trauma. For the entire series, ages ranged from 19 to 48 years (mean 31 years) with men accounting for 36 cases. Mean concentrations were as follows: plasma CE, 353 nmol/L (range 16.1-1,959); plasma COC, 386 nmol/L (range no measurable amount-1,455); and whole-blood ETOH, 36.5 mmol/L (range no measurable amount-110.9). The ratio CE:COC in plasma ranged 0.1 to 4.7 (mean 1.3). Concentrations of ETOH in whole blood showed significant negative correlation with plasma COC (r = -0.425, P < .01). In addition, plasma CE concentrations showed significant correlation with plasma COC (r = 0.422, P < .01). When available, urine concentrations of CE and COC showed significant correlation with their concentrations in plasma (r = 0.821, P < .01; and r = 0.569, P < .05, respectively). As in plasma, urine concentrations of CE showed significant correlation with urine COC (r = 0.831, P < .01).

Cocaine and cocaethylene binding to human tissues: a preliminary study.

The tissue binding of cocaine (COC) and cocaethylene (CE) was investigated by equilibrium dialysis of homogenates of whole human tissue supplemented with either COC or CE at concentrations of 10 and 50 microM for each drug. Concentrations of COC and CE were measured by high-pressure liquid chromatography. Kidney bound COC predominantly whereas serum bound it the least (about one tenth as much). In contrast, for CE, most binding was noted to brain with the least to serum (about one twentieth as much). Heart, placenta, and liver showed intermediate binding overall. The binding of COC and CE to these tissues may be important in understanding specific target-organ activity of both compounds.

Results of limited versus comprehensive toxicology screening in a university medical center.

Both comprehensive toxicology screening (COM) and limited toxicology screening (LIM) were performed on the same urine in 1,734 consecutive cases over a 6-month period at a university medical center. About half of the screens originated from inpatient services and half from outpatient services (mostly emergency department). In 71 % of the cases, there was agreement between the results of LIM and COM, with 47% of cases being negative. For 500 screens (accounting for 655 individual discrepant findings), at least one discrepancy was noted between LIM and COM. Of these, 399 cases demonstrated at least one finding with COM, but not with LIM ("false-negative" LIM). Topical anesthetics (including cocaine and cocaethylene), antiepileptics, and sympathomimetic amines accounted for 65% of findings. In contrast, 147 cases showed a finding with LIM, but not with COM ("false-positive" LIM), mostly amphetamines. In certain specified clinical circumstances, LIM may be a more cost effective and efficient approach than COM.

Cocaine and cocaethylene binding in human serum.

The binding of cocaine (COC) and cocaethylene (CE) in human serum was studied by equilibrium dialysis. Scatchard analysis suggested a high-affinity binder (Ka, 2.56 x 10(4)L/mol; Bo, 7.38 x 10(-5) mol/L) and a low-affinity binder (Ka, 4.47 x 10(3)L/mol; Bo, 2.77 x 10(-4) mol/L) for COC. Two high-affinity binders (Ka, 5.21 x 10(4) L/mol; Bo, 2.54 x 10(-5) mol/L; and Ka, 4.32 x 10(4) L/mol; Bo, 2.43 x 10(-5) mol/L) were discernible for CE. For both compounds additional, very-low-affinity, high-capacity (nonspecific) binding was also seen. Supplementation of serum with specific proteins suggested that the high-affinity binding was due to alpha-1-acid glycoprotein, whereas the low-affinity binding was due to albumin, inasmuch as such supplementation increased the ratio of bound to free drug for both COC and CE.