The effectiveness of teriparatide in the clinical practice--attenuation of the bone mineral density outcome by increasing age and bisphosphonate pretreatment.

BACKGROUND: Teriparatide is a potent anabolic agent for severe osteoporosis. OBJECTIVES: A primary objective of this retrospective study was to define the efficacy of teriparatide in terms of bone mineral density (BMD) changes and relief of back pain in clinical practice. METHODS: The patient population comprises 119 osteoporotic patients treated with teriparatide for median 539 (range 179-926) days. RESULTS: The mean BMD gain was 0.9% in the total hip (P = 0.0075), 2.1% in the femoral neck (P = 0.0006), and 8.5% in the lumbar spine (P = 0.0085). In the whole patient population age associated inversely with BMD changes in the total hip (P = 0.019) and in the femoral neck (P = 0.0036). A history of significant bisphosphonate pretreatment (n = 90) reduced BMD response in the total hip (P = 0.039). The total exposure of any prior bisphosphonate was negatively correlated with BMD response in the total hip (P = 0.0421). Half of the patients reported relief of back pain during the treatment. Leg pain, nausea, and dizziness were most frequent adverse concerns. CONCLUSIONS: Teriparatide works in clinical practice as well as in clinical trials. Younger subjects benefited more than older patients from teriparatide in the total hip and in the femoral neck. Bisphosphonate pretreatment attenuated teriparatide-induced BMD gain.

Teriparatide treatment complicated by malignant myeloma.

Recombinant human parathyroid hormone (1-34) (rhPTH 1-34), teriparatide (Forsteo in Europe), is a new compound that has been introduced and shown to be successful in the treatment of osteoporosis. The mechanisms of action include a pulsative influence on the RANKL/OPG system resulting in osteoblast activation and increased bone formation by teriparatide. In malignant myeloma there is an imbalance between osteoclast and osteoblast activity with involvement of the RANKL/OPG system among others. We report a case with monoclonal gammopathy of uncertain significance (MGUS) who developed malignant myeloma after teriparatide treatment and we suggest that in addition to malignant myeloma and smouldering myeloma, MGUS should also be considered contraindicated for teriparatide treatment.

Malignant myeloma in a patient after treatment for osteoporosis with teriparatide; a rare coincidence.

A breakthrough in understanding of mechanisms of bone structure regulation has brought about the introduction of the new synthetic recombinant human parathyroid hormone 1-34 (PTH1-34; Teriparatide) in the treatment of osteoporosis. These mechanisms, involving the RANKL, RANK, and osteoprotegerin system, are also known to be involved in malignant myeloma (MM) and tumor and bone metastasis development. We report a case in which MM was found after treatment of osteoporosis with teriparatide. We were unable to demonstrate any direct association between the MM and teriparatide treatment. However, it seemed intriguing that similar mechanisms are activated in the development of MM as those being working during teriparatide treatment. In the view of our case, we propose that MM by examination of serum protein fraction should be searched for prior to treatment with teriparatide as it is an exclusion criterion in teriparatide treatment of secondary osteoporosis. A search for other metastatic diseases prior to teriparatide treatment should eventually also be considered. The theoretical basis for our proposal is discussed.

A fatal doxepin poisoning associated with a defective CYP2D6 genotype.

It has been suggested that the polymorphism of the CYP2D6 gene can contribute to occurrence of fatal adverse effects. We therefore investigated postmortem toxicology cases of fatal drug poisonings related to CYP2D6 substrates, with the manner of death denoted as accidental or undetermined. CYP2D6 genotypes were determined in 11 consecutive cases with samples available for DNA analysis. A case of fatal doxepin poisoning with an undetermined manner of death was found to coincide with a completely nonfunctional CYP2D6 genotype (*3/*4), indicating a total absence of CYP2D6 enzyme and suggesting a poor metabolizer phenotype. The doxepin concentration was 2.4 mg/L, the concentration of nordoxepin 2.9 mg/L, and the doxepin/nordoxepin ratio 0.83, the lowest found among the 35 nordoxepin-positive postmortem cases analyzed during the same year. No alcohols or other drugs were detected in the case. The CYP2C19 genotype was determined as that of an extensive metabolizer. The high N-desmethylmetabolite concentration is not consistent with acute intoxication. It is therefore probable that the defective genotype has contributed to the death, possibly involving repeated high dosage of doxepin. Our case strongly emphasizes that a pharmacogenetic analysis in postmortem forensic setting may reveal new insight to the cause or manner of death.

Alcohol tax cuts and increase in alcohol-positive sudden deaths: a time-series intervention analysis.

AIMS: The impact of alcohol regulation changes in Finland during 2004 on alcohol-positive sudden deaths was analysed, focusing on: (1) removal of traveller's allowance quotas on alcohol imports from other European Union (EU) countries, (2) lowering of Finnish alcohol excise duty rates and (3) Estonia joining the EU. DESIGN: The impact of these changes was estimated using an autoregressive integrated moving average (ARIMA) analytical technique. Post-mortem forensic toxicology data were analysed over a 15-year period to account for seasonal and long-term variation. In all, the data comprised a weekly series of 33,782 alcohol-positive cases (at least 0.20 mg/g alcohol in blood) and a control series of 37,617 alcohol-negative cases. SETTING: Finland in 1990-2004. FINDINGS: The liberation of traveller's allowances had no material impact on alcohol-positive sudden deaths, but the impact of alcohol tax cuts in March 2004 was significant, resulting in an estimated eight additional alcohol-positive deaths per week, which is a 17% increase compared with the weekly average of 2003. The impact associated with Estonia joining the EU was not statistically significant. In the models applied to the control series of alcohol-negative deaths, none of the impact coefficients was statistically significant. CONCLUSIONS: Alcohol tax cuts were associated with an increase in the number of sudden deaths involving alcohol. This parallels the reported increases in alcohol consumption and alcohol-related causes of death in 2004 in Finland.

CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies.

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.

Newer antidepressants: evaluation of fatal toxicity index and interaction with alcohol based on Finnish postmortem data.

Finnish postmortem toxicology data from 1995 to 2002 was analyzed to obtain improved estimates of fatal toxicity indices for the newer antidepressants and to evaluate their interaction with alcohol. Altogether 284 fatal poisonings were attributed to 12 different newer antidepressants. Venlafaxine, mianserin, moclobemide, and mirtazapine were responsible for significantly more deaths than expected from their sales. Their fatal toxicity indices were higher than those of selective serotonin reuptake inhibitors (SSRIs) but lower than those of tricyclic antidepressants. In fatal poisonings involving alcohol in combination with venlafaxine, mianserin, moclobemide, or mirtazapine, the median blood alcohol concentration (BAC) ranged from 2.35 to 2.7 mg/g, whereas in those involving alcohol in combination with citalopram or fluoxetine the median BAC was 2.9 and 3.4 mg/g, respectively. The BAC was significantly lower in venlafaxine-related deaths than in those involving fluoxetine or citalopram. We conclude that among the newer antidepressants differences are present both in toxicity and in interaction potential with alcohol. The SSRIs appear to present a low risk of fatal poisoning when taken alone or in combination with alcohol, whereas venlafaxine is associated with an elevated risk.

Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood.

Tramadol is an opioid drug metabolised in phase I by cytochrome P450 (CYP) enzymes, of which CYP2D6 is mainly responsible for the O-demethylation of tramadol, but is not involved in N-demethylation. Defects in the genes encoding drug metabolising enzymes (DMEs) may lead to adverse drug effects, even to death. To aid interpretation of the forensic toxicology results, we studied how the genetic variation of the CYP2D6 gene is reflected in tramadol metabolite ratios found in post-mortem samples. In 33 Finnish autopsy cases where tramadol was found, we analysed both the CYP2D6 genotype and the concentrations of tramadol and its metabolites O- and N-demethyltramadol. As expected, we found a correlation between the number of functional CYP2D6 alleles and the ratio of tramadol to O-demethyltramadol. We also found a correlation between the number of functional alleles and the ratio of tramadol to N-demethyltramadol. This can be explained by the complementary nature of the two main tramadol demethylation pathways. No known CYP2D6 inhibitors were associated with exceptional metabolic ratios. Furthermore, no accidental tramadol poisonings were associated with a defective CYP2D6 gene. Our results on the tramadol are among the first to demonstrate that genetic variation in drug metabolising enzymes can be analysed in post-mortem blood, and that it correlates well with the parent drug to metabolite ratios. The results also suggest that genetic factors play, in general, a dominant role over other factors in the metabolism of individual drugs.

Interaction of alcohol and drugs in fatal poisonings.

In Finnish data from 1995-2000, 1006 fatal poisonings due to alcohol (ethanol), a single drug or both were statistically analysed in retrospect to evaluate the interaction between alcohol and drugs. In 53% of these cases, low concentrations of some common benzodiazepines were present. The median postmortem blood alcohol concentration (BAC) was 3.3 percent per thousand (w/w) in the 615 alcohol poisonings, but significantly lower, ranging from 1.3 to 1.7 percent per thousand, when promazine, doxepin, amitriptyline or propoxyphene were found together with alcohol. When levomepromazine, temazepam or zopiclone were present, the median BAC was also significantly lower, 2.5-2.7 percent per thousand. Citalopram and diltiazem did not exhibit a significant effect. The median BAC was significantly lower in cases with high concentrations than in those with low concentrations of a drug (excluding citalopram), suggesting a positive concentration-effect relationship. Fatal toxicity indices (FTIs) were calculated by relating the number of deaths caused by a drug to the corresponding sales figures. Promazine had an extremely high FTI, followed by levomepromazine, propoxyphene, doxepin and amitriptyline. The other drugs had relatively low FTIs. The results reflect not only the acute toxicity of a given drug-alcohol combination but also the manners of use and abuse of these drugs.

Alcohol and benzodiazepines in fatal poisonings.

BACKGROUND: Postmortem forensic toxicology frequently finds alcohol both alone and in combination with drugs. Although benzodiazepines are generally considered safe, they are considered dangerous with alcohol. METHODS: A retrospective statistical analysis of alcohol and benzodiazepine concentrations in postmortem blood samples included 808 cases diagnosed as fatal alcohol or drug intoxication involving (1) ethanol alone; (2) ethanol with temazepam; or (3) ethanol with any combination of diazepam, chlordiazepoxide, and nordazepam. RESULTS: The median concentration of ethanol was 3.3 per thousand in cases with ethanol alone and 3.5 per thousand when diazepam was present, but it was significantly lower, only 2.5 per thousand, when temazepam was present in the blood. Furthermore, the median concentration of ethanol was 2.2 per thousand in cases with high concentrations (>0.9 mg/liter) of temazepam and 2.7 per thousand in cases with therapeutic (< or =0.9 mg/liter) concentrations. CONCLUSIONS: Diazepam and chlordiazepoxide pose a smaller risk of death by poisoning than does temazepam when given as a hypnotic to patients suffering from alcoholism.