Kevin J Gingrich, M.D.

Anesthetic complications in pediatric patients undergoing cochlear implantation
Yeh, Joseph S; Mooney, Kimberly L; Gingrich, Kevin; Kim, Jung T; Lalwani, Anil K
2011 Oct;121(10):2240-2244, Laryngoscope
OBJECTIVES/HYPOTHESIS: Cochlear implantation (CI) is effective in the treatment of childhood sensorineural hearing loss and is associated with minimal surgical complications. We investigated the incidence of anesthetic complications in young patients undergoing general anesthesia for CI. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review of 123 patients younger than 18 years, who underwent CI between 2007 and 2008, was conducted for identification of intra- and postoperative anesthesia-related complications. The relation of collected variable to the complication events was analyzed using logistic regression. RESULTS: Of the 123 CI procedures, eight patients had nine anesthesia-related complications, yielding a complication rate of 6.5% and included the following: postoperative wheezing/stridor (5 cases), laryngospasm (3 cases), and emesis during inhalational induction (1 case). Divided by age group, 12 patients were <12 months with one complication (8%), 18 patients were between 1 and 2 years with one complication (5.6%), 35 patients were between 2 and 5 years with one complication (3%), 39 patients were between 5 and 12 years with five complications (13%), and 19 patients were older than 12 years with no complication (0%). Logistic regression failed to identify a significant association of any collected variable(s) with the observed complications. The incidence of complications is similar to that previously reported in elderly patients (4.3%) (Pearson chi(2) , P = .523). CONCLUSIONS: General anesthesia is well tolerated by pediatric patients undergoing CI, even under 1 year of age. Significant perioperative complications are primarily respiratory, are usually free of long-term sequelae, and occur with an incidence similar to other reported age groups
— id: 137895, year: 2011, vol: 121, page: 2240, stat: Journal Article,

Pentobarbital inhibition of human recombinant alpha P/Q-type voltage-gated calcium channels involves slow, open channel block
Schober, A; Sokolova, E; Gingrich, K J
2010 Sep;161(2):365-383, British journal of pharmacology
BACKGROUND AND PURPOSE Pre-synaptic neurotransmitter release is largely dependent on Ca(2+) entry through P/Q-type (Ca(V)2.1) voltage-gated Ca(2+) channels (PQCCs) at most mammalian, central, fast synapses. Barbiturates are clinical depressants and inhibit pre-synaptic Ca(2+) entry. PQCC barbiturate pharmacology is generally unclear, specifically in man. The pharmacology of the barbiturate pentobarbital (PB) in human recombinant alpha(1A) PQCCs has been characterized. EXPERIMENTAL APPROACH PB effects on macroscopic Ca(2+)(I(Ca)) and Ba(2+)(I(Ba)) currents were studied using whole-cell patch clamp recording in HEK-293 cells heterologously expressing (alpha(1A))(human)(beta(2a)alpha(2)delta-1)(rabbit) PQCCs. KEY RESULTS PB reversibly depressed peak current (I(peak)) and enhanced apparent inactivation (fractional current at 800 ms, r(800)) in a concentration-dependent fashion irrespective of charge carrier (50% inhibitory concentration: I(peak), 656 microM; r(800), 104 microM). Rate of mono-exponential I(Ba) decay was linearly dependent on PB concentration. PB reduced channel availability by deepening non-steady-state inactivation curves without altering voltage dependence, slowed recovery from activity-induced unavailable states and produced use-dependent block. PB (100 microM) induced use-dependent block during physiological, high frequency pulse trains and overall depressed PQCC activity by two-fold. CONCLUSION AND IMPLICATIONS The results support a PB pharmacological mechanism involving a modulated receptor with preferential slow, bimolecular, open channel block (K(d)= 15 microM). Clinical PB concentrations (<200 microM) inhibit PQCC during high frequency activation that reduces computed neurotransmitter release by 16-fold and is comparable to the magnitude of Ca(2+)-dependent facilitation, G-protein modulation and intrinsic inactivation that play critical roles in PQCC modulation underlying synaptic plasticity. The results are consistent with the hypothesis that PB inhibition of PQCCs contributes to central nervous system depression underlying anticonvulsant therapy and general anaesthesia
— id: 111981, year: 2010, vol: 161, page: 365, stat: Journal Article,

In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylme thoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist
Atack, John R; Maubach, Karen A; Wafford, Keith A; O'Connor, Desmond; Rodrigues, A David; Evans, David C; Tattersall, F David; Chambers, Mark S; MacLeod, Angus M; Eng, Wai-Si; Ryan, Christine; Hostetler, Eric; Sanabria, Sandra M; Gibson, Raymond E; Krause, Stephen; Burns, H Donald; Hargreaves, Richard J; Agrawal, Nancy G B; McKernan, Ruth M; Murphy, M Gail; Gingrich, Kevin; Dawson, Gerard R; Musson, Donald G; Petty, Kevin J
2009 Nov;331(2):470-484, Journal of pharmacology & experimental therapeutics
3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylme thoxy)-pyrazolo[1,5-d][1,2,4]triazine (MRK-016) is a pyrazolotriazine with an affinity of between 0.8 and 1.5 nM for the benzodiazepine binding site of native rat brain and recombinant human alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. It has inverse agonist efficacy selective for the alpha5 subtype, and this alpha5 inverse agonism is greater than that of the prototypic alpha5-selective compound 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-hdyl)methyloxy]-1,2 ,4-triazolo[3,4-a]phthalazine (alpha5IA). Consistent with its greater alpha5 inverse agonism, MRK-016 increased long-term potentiation in mouse hippocampal slices to a greater extent than alpha5IA. MRK-016 gave good receptor occupancy after oral dosing in rats, with the dose required to produce 50% occupancy being 0.39 mg/kg and a corresponding rat plasma EC(50) value of 15 ng/ml that was similar to the rhesus monkey plasma EC(50) value of 21 ng/ml obtained using [(11)C]flumazenil positron emission tomography. In normal rats, MRK-016 enhanced cognitive performance in the delayed matching-to-position version of the Morris water maze but was not anxiogenic, and in mice it was not proconvulsant and did not produce kindling. MRK-016 had a short half-life in rat, dog, and rhesus monkey (0.3-0.5 h) but had a much lower rate of turnover in human compared with rat, dog, or rhesus monkey hepatocytes. Accordingly, in human, MRK-016 had a longer half-life than in preclinical species ( approximately 3.5 h). Although it was well tolerated in young males, with a maximal tolerated single dose of 5 mg corresponding to an estimated occupancy in the region of 75%, MRK-016 was poorly tolerated in elderly subjects, even at a dose of 0.5 mg, which, along with its variable human pharmacokinetics, precluded its further development
— id: 109083, year: 2009, vol: 331, page: 470, stat: Journal Article,

Pentobarbital produces activation and block of {alpha}1{beta}2{gamma}2S GABAA receptors in rapidly perfused whole cells and membrane patches: divergent results can be explained by pharmacokinetics
Gingrich, Kevin J; Burkat, Paul M; Roberts, William A
2009 Feb;133(2):171-188, Journal of general physiology
Millimolar concentrations of the barbiturate pentobarbital (PB) activate gamma-aminobutyric acid (GABA) type A receptors (GABARs) and cause blockade reported by a paradoxical current increase or 'tail' upon washout. To explore the mechanism of blockade, we investigated PB-triggered currents of recombinant alpha(1)beta(2)gamma(2S) GABARs in whole cells and outside-out membrane patches using rapid perfusion. Whole cell currents showed characteristic bell-shaped concentration dependence where high concentrations triggered tail currents with peak amplitudes similar to those during PB application. Tail current time courses could not be described by multi-exponential functions at high concentrations (> or =3,000 microM). Deactivation time course decayed over seconds and was slowed by increasing PB concentration and application time. In contrast, macropatch tail currents manifested eightfold greater relative amplitude, were described by multi-exponential functions, and had millisecond rise times; deactivation occurred over fractions of seconds and was insensitive to PB concentration and application time. A parsimonious gating model was constructed that accounts for macropatch results ('patch' model). Lipophilic drug molecules migrate slowly through cells due to avid partitioning into lipophilic subcellular compartments. Inclusion of such a pharmacokinetic compartment into the patch model introduced a slow kinetic component in the extracellular exchange time course, thereby providing recapitulation of divergent whole cell results. GABA co-application potentiated PB blockade. Overall, the results indicate that block is produced by PB concentrations sixfold lower than for activation involving at least three inhibitory PB binding sites, suggest a role of blocked channels in GABA-triggered activity at therapeutic PB concentrations, and raise an important technical question regarding the effective rate of exchange during rapid perfusion of whole cells with PB
— id: 96467, year: 2009, vol: 133, page: 171, stat: Journal Article,

Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice
Haile, Michael; Limson, Fred; Gingrich, Kevin; Li, Yong-Sheng; Quartermain, David; Blanck, Thomas; Bekker, Alex
2009 Apr;21(2):140-144, Journal of neurosurgical anesthesiology
BACKGROUND: Cognitive changes associated with moderate hypoxia may be related to the elevation of cytosolic calcium (Ca) levels which may, in turn, affect neurotransmitter synthesis and metabolism. We tested whether treatment with nimodipine (NIMO), an L-type Ca channel blocker, would preserve working memory after hypoxic hypoxia. METHODS: We randomized 157 Swiss-Webster, 30 to 35 g mice (6 to 8 wk) to 6 groups, which were exposed to the following gas mixtures for 1 hour: (1) O2 21%; (2) O2 21% followed by 0.1 mg/kg of subcutaneous NIMO; (3) O2 21% followed by vehicle (60% polyethylene glycol/40% methanol); (4) O2 10%; (5) O2 10% then NIMO; (6) O2 10% then vehicle. The Object Recognition Test (ORT) was given once either on Day 1 or Day 7 to assess changes in short-term memory. ORT exploits the tendency of mice to prefer novel over familiar objects. Two identical objects were placed in an arena for 15 minutes of training. During the testing 1 hour later, one of the objects was replaced by a new object. Recognition Index (RI) was used to compare performance. It is defined as the time spent exploring the novel object divided by the time spent exploring both objects, the novel plus the familiar, and this ratio is converted to a percentage. RI was analyzed with analysis of variance. Tukey Honestly Significant Difference tests were used for post hoc comparisons when appropriate. P values <0.05 were considered significant. RESULTS: RI for the control group was 68.3% (SE+/-3.6%). RI was 53.7% (SE+/-3.8%) for the 10% O2 group on the first posttreatment day. O2 saturation (SpO2) for the hypoxic group was 71.7% (SE+/-0.5%). By Day 7, RI for the 10% O2 group increased to 64.2% (SE+/-4.7%), which was not significantly different from control. On Day 1, RI was 68.6% (SE+/-5.2%) for hypoxic rodents treated with NIMO. These results were statistically significant. Low RI indicates impaired working memory and high RI indicates intact working memory. These results suggest that NIMO prevented impairment of working memory after moderate hypoxia. CONCLUSIONS: NIMO reverses the disturbance of short-term working memory caused by moderate hypoxia in mice. The results may have implications for cognitive changes linked to Ca homeostasis in the postoperative period
— id: 132606, year: 2009, vol: 21, page: 140, stat: Journal Article,

Physostigmine reverses cognitive dysfunction caused by moderate hypoxia in adult mice
Bekker, Alex; Haile, Michael; Gingrich, Kevin; Wenning, Leslie; Gorny, Alex; Quartermain, David; Blanck, Thomas
2007 Sep;105(3):739-743, Anesthesia & analgesia
BACKGROUND: Cognitive changes associated with moderate hypoxia in rodents may result from the diminished functioning of central cholinergic neurotransmission. We designed this study to examine whether treatment with physostigmine (PHY), an acetylcholinesterase inhibitor, could improve the impairment of working memory after hypoxic hypoxia. METHODS: We randomized 90 Swiss Webster, 30-35 g mice (6-8 wks) to three hypoxia groups at fraction of inspired oxygen, FiO2 = 0.10 (1. no treatment; 2. PHY 0.1 mg/kg intraperitoneally administered immediately before; or 3. after hypoxia), or to two room air groups (given either no treatment or PHY after an insult). An object recognition test was used to assess short-term memory function. The object recognition test exploits the tendency of mice to prefer exploring novel objects in an environment when a familiar object is also present. During the 15 min training trial, two identical objects were placed in two defined sites of the box. During the test trial performed 1 h later, one of the objects was replaced by a new object with a different shape. The time spent exploring the two objects was automatically recorded by a video camera and associated software. The performance was analyzed with ANOVA, followed by post hoc comparisons using the Newman-Keuls test when appropriate. P values <0.05 were considered significant. RESULTS: Untreated mice subjected to hypoxia at Fio2 = 0.1 spent significantly less time exploring a novel object on testing day 1 than did untreated mice breathing room air. Performance of the mice subjected to hypoxia, who received physostigmine after, but not before, the insult did not differ from the control group. CONCLUSION: Moderate hypoxia impairs rodents' performance in a working memory task. It appears that changes are transient, because the cognitive functioning of the mice returned to the baseline level 7 days after treatment. Postinsult administration of PHY prevented deterioration of cognitive function. An increased level of acetylcholine in the central nervous system may be responsible for the improved performance of the hypoxia-treated mice
— id: 86616, year: 2007, vol: 105, page: 739, stat: Journal Article,

Isoflurane inhibition of recombinant cardiac L-type Ca2+ channels
Gingrich, K; Blanck, T
2007 JAN ;108(11):100A-100A, Biophysical journal
— id: 71387, year: 2007, vol: 108, page: 100A, stat: Journal Article,

Halothane inhibition of recombinant cardiac L-type Ca2+ channels expressed in HEK-293 cells
Gingrich, Kevin J; Tran, Son; Nikonorov, Igor M; Blanck, Thomas J
2005 Dec;103(6):1156-1166, Anesthesiology
BACKGROUND: Volatile anesthetics depress cardiac contractility, which involves inhibition of cardiac L-type calcium channels. To explore the role of voltage-dependent inactivation, the authors analyzed halothane effects on recombinant cardiac L-type calcium channels (alpha1Cbeta2a and alpha1Cbeta2aalpha2/delta1), which differ by the alpha2/delta1 subunit and consequently voltage-dependent inactivation. METHODS: HEK-293 cells were transiently cotransfected with complementary DNAs encoding alpha1C tagged with green fluorescent protein and beta2a, with and without alpha2/delta1. Halothane effects on macroscopic barium currents were recorded using patch clamp methodology from cells expressing alpha1Cbeta2a and alpha1Cbeta2aalpha2/delta1 as identified by fluorescence microscopy. RESULTS: Halothane inhibited peak current (I(peak)) and enhanced apparent inactivation (reported by end pulse current amplitude of 300-ms depolarizations [I300]) in a concentration-dependent manner in both channel types. alpha2/delta1 coexpression shifted relations leftward as reported by the 50% inhibitory concentration of I(peak) and I300/I(peak)for alpha1Cbeta2a (1.8 and 14.5 mm, respectively) and alpha1Cbeta2aalpha2/delta1 (0.74 and 1.36 mm, respectively). Halothane reduced transmembrane charge transfer primarily through I(peak) depression and not by enhancement of macroscopic inactivation for both channels. CONCLUSIONS: The results indicate that phenotypic features arising from alpha2/delta1 coexpression play a key role in halothane inhibition of cardiac L-type calcium channels. These features included marked effects on I(peak) inhibition, which is the principal determinant of charge transfer reductions. I(peak) depression arises primarily from transitions to nonactivatable states at resting membrane potentials. The findings point to the importance of halothane interactions with states present at resting membrane potential and discount the role of inactivation apparent in current time courses in determining transmembrane charge transfer
— id: 61856, year: 2005, vol: 103, page: 1156, stat: Journal Article,

The distribution of cocaine in mice differs by age and strain
McCarthy, Lois E; Mannelli, Paolo; Niculescu, Michelle; Gingrich, Kevin; Unterwald, Ellen M; Ehrlich, Michelle E
2004 Nov-Dec;26(6):839-848, Neurotoxicology & teratology
Few studies have examined the influence of the age and the strain of mouse on the pharmacokinetics of psychostimulants, or the role of pharmacokinetics in age-related differences in drug responses. The present study compared concentrations of cocaine, and its metabolite, benzoylecgonine (BZE), in the blood and brain of early (P35) and later (P42) periadolescent and adult (P63) CD-1 and C57BL/6 male mice 15 min after acute intraperitoneal injection of cocaine (20 mg/kg). Brain levels of cocaine and BZE after seven daily cocaine injections in CD-1 and C57BL/6 mice beginning on P35 and on P63 were also measured. P35 periadolescents of both strains had lower blood cocaine levels than did the adults, but only C57BL/6 periadolescents had lower brain cocaine levels than the adults. C57BL/6 mice of both ages had higher blood cocaine levels than did the corresponding CD-1 mice. Concomitant with lower cocaine levels, periadolescent CD-1 mice had higher blood BZE levels than the adults, suggesting that periadolescents may metabolize cocaine faster. Brain cocaine levels in P42 C57BL/6 mice were similar to those of adults. Cocaine-induced activity did not differ between periadolescent and adult CD-1 mice after a single injection of cocaine, whereas periadolescent C57BL/6 mice had lower activity levels than did the adults after a single cocaine injection. Periadolescent CD-1 mice exhibited higher levels of locomotor activity following cocaine injection than did periadolescent C57BL/6 mice. Following chronic cocaine administration, cocaine and BZE levels in the brains of periadolescent and adult mice did not differ from each other in either strain. However, brain cocaine levels at both ages were lower in CD-1 mice than in C57BL/6 mice. In conclusion, the age and the strain of mouse significantly affect the levels of cocaine obtained in brain and blood following acute administration. Our data are consistent with the notion that CD-1 and C57BL/6 mice metabolize cocaine faster during the early periadolescent period than as adults. Furthermore, potentially important strain differences between CD-1 and C57BL/6 mice were noted in cocaine levels following acute and chronic cocaine administration, and in locomotor activity following acute cocaine administration
— id: 48901, year: 2004, vol: 26, page: 839, stat: Journal Article,