Transcutaneous PCO2 for Exercise Gas Exchange Efficiency in Chronic Obstructive Pulmonary Disease.

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiological dead space (VD/VT). Noninvasive methods for accurate VD/VT assessment during exercise in patients are lacking. The current study sought to compare transcutaneous PCO2 (TcPCO2) with the gold standard-arterial PCO2 (PaCO2)-and other available methods (end tidal CO2 and the Jones equation) for estimating VD/VT during incremental exercise in COPD. Ten COPD patients completed a symptom limited incremental cycle exercise. TcPCO2 was measured by a heated electrode on the ear-lobe. Radial artery blood was collected at rest, during unloaded cycling (UL) and every minute during exercise and recovery. Ventilation and gas exchange were measured breath-by-breath. Bland-Altman analysis examined agreement of PCO2 and VD/VT calculated using PaCO2, TcPCO2, end-tidal PCO2 (PETCO2) and estimated PaCO2 by the Jones equation (PaCO2-Jones). Lin's Concordance Correlation Coefficient (CCC) was assessed. 114 measurements were obtained from the 10 COPD subjects. The bias between TcPCO2 and PaCO2 was 0.86 mmHg with upper and lower limit of agreement ranging -2.28 mmHg to 3.99 mmHg. Correlation between TcPCO2 and PaCO2 during rest and exercise was r2=0.907 (p < 0.001; CCC = 0.941) and VD/VT using TcPCO2 vs. PaCO2 was r2=0.958 (p < 0.0001; CCC = 0.967). Correlation between PaCO2-Jones and PETCO2 vs. PaCO2 were r2=0.755, 0.755, (p < 0.001; CCC = 0.832, 0.718) and for VD/VT calculation (r2=0.793, 0.610; p < 0.0001; CCC = 0.760, 0.448), respectively. The results support the accuracy of TcPCO2 to reflect PaCO2 and calculate VD/VT during rest and exercise, but not in recovery, in COPD patients, enabling improved accuracy of noninvasive assessment of gas exchange inefficiency during incremental exercise testing.

79-year Old Man on Nivolumab with Itchy Erythematous Patches.

A 79-year-old white man presented with an ulcerated chest wall lesion developing from an existing mole. After definitive surgery, it proved to be a malignant melanoma and staged as T4N1M0. He received 1 year of adjuvant therapy with nivolumab. Starting on the last month of adjuvant nivolumab treatment, he developed itchy erythematous patches on his left posterior shoulder that spread over his trunk, arms, and thighs.

Does Delayed Excretion of Therapeutic 131I-MIBG Interfere with a 123I-MIBG Diagnostic Scan 6 Weeks After the Therapy?

131I-metaiodobenzylguanidine (131I-MIBG) is a theranostic agent useful for treatment of neuroendocrine malignancies. In this case, a child with a Curie score of 21 was administered 17.871 GBq (483 mCi) of 131I-MIBG. The elimination half-life progressively increased from 23 h to 77 h during the 11 d that the patient was hospitalized for radiation isolation. Six weeks after the posttherapy scan, a survey with an ion-chamber device yielded readings of 0.3 µSv/h (0.03 mR/h) on contact with spinal regions that had shown increased uptake on the scan. A planar image obtained using the 131I setting and a high-energy collimator did not demonstrate any focal uptake. 123I-MIBG was administered, and the 24-h scan was of diagnostic quality, without degradation from the remaining 131I-MIBG. Additional study is needed on whether the Curie score affects elimination of 131I-MIBG and on whether the period of hospitalized radiation isolation needs to be extended.

Pharmacogenetics of healthy volunteers in Puerto Rico.

Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer's disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island.

Genetic variants of the drug-metabolizing enzyme CYP2D6 in Puerto Rican psychiatry patients: a preliminary report and potential implications for breast cancer patients.

BACKGROUND: The CYP2D6 liver enzyme, which metabolizes 25-30% of common medications, is highly polymorphic. Existing studies of Hispanics have focused on Mexicans and Mexican-Americans. The goal of the study was to identify the CYP2D6 alleles associated with reduced or negligible activities present in the Puerto Rican population. METHODS: The study cohort comprised 40 Puerto Rican psychiatric patients referred because of suspected intolerance of drugs metabolized by CYP2D6, and five subjects without suspected adverse responses to these drugs. All subjects had both parents and all grandparents born in Puerto Rico. Genomic DNA was queried for 27 CYP2D6 alleles using the Roche AmpliChip P450 test. RESULTS: A total of 12 alleles were identified. The most common alleles were CYP2D6*1 > *2 > *4 > *41. The inactive alleles were *4 > * 5 > * 31 >*40; reduced activity alleles were *10 >* 17 > *9* = *29; active alleles were *1 > *2 > *35. Two subjects carried the rare *31 allele. Only one subject carried two non-functional alleles (CYP2D6*5/*40), and was predicted to be a poor metabolizer. CONCLUSIONS: Any conclusions should be interpreted with caution given the small population sample investigated. Nonetheless, our findings strongly suggest that Puerto Ricans exhibit distinct CYP2D6 allele frequencies and harbor a non-functional allele that is rare or absent in other populations and are highly valuable for the emerging practice of Personalized Medicine in admixed populations like Puerto Ricans.

Discovery of the nonfunctional CYP2D6 31 allele in Spanish, Puerto Rican, and US Hispanic populations.

BACKGROUND: CYP2D6 31 (4042G>A, R(440)H) is an allelic variant of the highly polymorphic cytochrome P450 2D6 enzyme that has been associated with reduced functional activity. The US Food and Drug Administration (FDA)-cleared AmpliChip CYP450 test detects the 4042G>A single nucleotide polymorphism (SNP) but an allele assignment could not be made in two Spanish and two Puerto Rican individuals heterozygous for 4042G>A, resulting in no-calls. We aimed to resolve the CYP2D6 31 no-calls, determine the allele haplotype, and corroborate that CYP2D6 31 is associated with a poor metabolizer phenotype. METHODS: CYP2D6 genotyping was carried out using the AmpliChip CYP450 test and long-range polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) platforms. Allele haplotype was determined by cloning and sequence analysis. Allele frequencies were determined in five population samples. RESULTS: A 6.6-kb long-range PCR product comprising the entire CYP2D6 gene and flanking regions was sequenced to determine the CYP2D6 31 haplotype. Identical sequences were obtained from both Puerto Ricans selected for sequence analysis. One Spanish individual with a CYP2D6 4/31 genotype was phenotyped as a poor metabolizer with the CYP2D6 probe drug dextromethorphan (urinary ratio DM/DX=0.71). The frequency of CYP2D6 31 was determined in 176 Spanish (0.57%), 50 Puerto Rican (2.0%), and 150 Hispanic (0.33%) people. CYP2D6 31 was absent in 237 North American Caucasians and 154 African Americans. CONCLUSIONS: CYP2D6 31 was associated with poor metabolism of dextromethorphan in vivo, which is consistent with a previous report classifying this allelic variant as nonfunctional. The discovery of CYP2D6 31 in Spanish people only (or of Spanish ancestry) suggests that it may contribute to CYP2D6 variability in individuals of Spanish ancestry.

Recent developments in the therapeutic potential of cannabinoids.

OBJECTIVE: To examine the recent evidence that marijuana and other cannabinoids have therapeutic potential. METHODS: Literature published since 1997 was searched using the following terms: cannabinoid, marijuana, THC, analgesia, cachexia, glaucoma, movement, multiple sclerosis, neurological, pain, Parkinson, trial, vomiting. Qualifying clinical studies were randomized, double-blind, and placebo-controlled. Selected open-label studies and surveys are also discussed. RESULTS: A total of 15 independent, qualifying clinical trials were identified, of which only three had more than 100 patients each. Two large trials found that cannabinoids were significantly better than placebo in managing spasticity in multiple sclerosis. Patients self-reported greater sense of motor improvement in multiple sclerosis than could be confirmed objectively. In smaller qualifying trials, cannabinoids produced significant objective improvement of tics in Tourette's disease, and neuropathic pain. A new, non-psychotropic cannabinoid also has analgesic activity in neuropathic pain. No significant improvement was found in levodopa-induced dyskinesia in Parkinson's Disease or post-operative pain. No difference from active placebo was found for management of cachexia in a large trial. Some immune system parameters changed in HIV-1 and multiple sclerosis patients treated with cannabinoids, but the clinical significance is unknown. Quality of life assessments were made in only three of 15 qualifying clinical trials. CONCLUSION: Cannabinoids may be useful for conditions that currently lack effective treatment, such as spasticity, tics and neuropathic pain. New delivery systems for cannabinoids and cannabis-based medicinal extracts, as well as new cannabinoid derivatives expand the options for cannabinoid therapy. More well-controlled, large clinical tests are needed, especially with active placebo.